CN120641090A

CN120641090A - Methods of administering Soanfito to lactating women

Info

Publication number: CN120641090A
Application number: CN202380093298.2A
Authority: CN
Inventors: H·塔布托
Original assignee: Axum Malta Ltd
Current assignee: Axum Malta Ltd
Priority date: 2022-12-30
Filing date: 2023-12-29
Publication date: 2025-09-12
Also published as: WO2024145545A3; EP4642446A2; MX2025007535A; KR20250129075A; AU2023415568A1; WO2024145545A2

Abstract

According to some embodiments, provided herein are methods for reducing the likelihood of adverse events caused by Soanfitol in an infant fed breast milk obtained from a subject treated with Soanfitol, comprising: orally administering Soanfitol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject at least about 5 hours after administering Soanfitol to the subject, thereby reducing the likelihood of Soanfitol adverse events in the infant.

Description

Methods of administering triamcinolone acetonide to lactating women

Priority statement

The present application claims the benefit of U.S. application Ser. No. 18/148,682, now U.S. patent No. 11,771,666, U.S. application Ser. No. 18/176,816, now U.S. patent No. 11,771,667, U.S. application Ser. No. 18/176,855, now U.S. patent No. 11,793,776, U.S. application Ser. No. 18/176,860, now U.S. patent No. 11,779,554, U.S. application Ser. No. 18/323,229, U.S. application Ser. No. 18/323, U.S. No. 2023 to 5 month 24, U.S. application Ser. No. 18/323,232, U.S. application Ser. No. 18/323,236, U.S. 18/491, U.S. application Ser. No. 18/491, U.S. 20, U.S. No. 2023 to 10 month 20, U.S. No. 18/301, 2023 to 20, and U.S. 20, U.S. 18/491, and 491, each of which are incorporated herein by reference.

Technical Field

The present invention relates to methods of administering to a lactating subject triamcinolone acetonide (solriamfetol) while reducing the likelihood of adverse events caused by triamcinolone acetonide in a breast-fed infant from the subject.

Background

Sofosamil is a selective dopamine and norepinephrine reuptake inhibitor that has been licensed in the United states for improving wakefulness in adult subjects with Excessive Daytime Sleepiness (EDS) associated with narcolepsy or Obstructive Sleep Apnea (OSA). Sofosamitraz has proven useful in the treatment of a variety of disorders including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorders, fibromyalgia, and the like.

Pharmacokinetic studies have demonstrated rapid absorption and high oral bioavailability of the thaumatin in the animals tested, and exposure (maximum serum concentration and area under the concentration-time curve [ AUC ]) is dose proportional.

The present invention overcomes the shortcomings in the art by providing a method of administering to a lactating subject triamcinolone acetonide while reducing the likelihood of adverse events caused by triamcinolone acetonide in a breast-fed infant from the subject.

Disclosure of Invention

The present invention relates to the development of methods of reducing the likelihood of adverse events caused by suafrican tols from breast-fed infants of a subject. The invention further relates to a method of reducing exposure to suofatuo in breast-fed infants obtained from a subject treated with suofatuo.

Accordingly, one aspect of the present invention relates to a method of reducing exposure to suafrican tray of a breast-fed infant obtained from a subject treated with suafrican tray, comprising orally administering to the subject the suafrican tray at a daily dose of about 37.5mg to about 300mg, and feeding to the infant breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administration of the suafrican tray to the subject, thereby reducing exposure to the infant to the suafrican tray.

Another aspect of the invention relates to a method for reducing the likelihood of an adverse event caused by suafrican tray in a breast-fed infant obtained from a subject treated with suafrican tray, comprising orally administering to the subject the suafrican tray at a daily dose of between 37.5mg and 300mg, and feeding to the infant breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administration of the suafrican tray to the subject, thereby reducing the likelihood of an adverse event caused by the suafrican tray in the infant. In some embodiments, the daily dose of suofetto is 150mg.

One aspect of the invention relates to a method of treating a disorder treatable with suafrican tray in a subject producing breast milk for feeding an infant, comprising orally administering to the subject a daily dose of between 37.5mg and 300mg of suafrican tray, and reducing exposure to suafrican tray and/or reducing the likelihood of adverse events in a breast-fed infant from the subject, comprising feeding to the infant breast milk from the subject at least about 2 hours (e.g., at least about 3,4, or 5 hours) after administration of suafrican tray to the subject. The disorder treatable with suofatuo may be, but is not limited to, narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit/hyperactivity disorder, cognitive impairment or binge eating disorders.

Another aspect of the invention relates to a method of avoiding exposure of an infant of a nursing mother being treated with sorafenib to peak concentrations of cord An Feituo excreted in breast milk, such method comprising not feeding to the infant breast milk obtained within at least about 3.5 hours (e.g., at least about 4 or 5 hours) of the mother receiving a once daily oral dose of sorafenib, wherein T _max excreted in the breast milk is about 1.1 hours.

A further aspect of the invention relates to a method of reducing the exposure of a baby receiving breast milk from a nursing mother to thaumatin from breast milk, the nursing mother being treated with a once daily dose of about 37.5mg to about 300mg of thaumatin to treat a disorder suitable for treatment with thaumatin, such method comprising feeding the baby with breast milk obtained from the mother at least about 5 hours after administration of thaumatin to the mother, wherein the baby's exposure to thaumatin is reduced by at least about 50% compared to the exposure that would result from feeding the baby with breast milk obtained from the mother less than 5 hours after administration of thaumatin.

Further aspects of the invention relate to a method of treating excessive daytime sleepiness in a nursing mother, wherein an infant is at risk of adverse events caused by excessive daytime sleepiness in the mother and the nursing mother wishes to breast feed the infant, comprising (a) determining whether the total score of the mother's Ai Puwo somnolence scale (ESS) and the mother experience sleep onset while taking care of the infant, (b) providing to the mother having a total score of ESS of 15 or more and experiencing sleep onset while taking care of the infant, 37.5mg once daily (if excessive daytime sleepiness is associated with obstructive sleep apnea) or 75mg once daily (if excessive daytime sleepiness is associated with narcolepsy) of a starting dose of suofurant and multiplying the dose at time intervals of at least 3 days up to 150mg once daily, wherein the elimination half-life of suofurant in the plasma of the mother in post-partum or nursing mother is about 5 hours, and (c) providing to the infant a maximum of breast milk 1 in cradle of at least about 3.5 hours (e.4 or 5 hours after administering to the infant, whereby a maximum of breast milk 1 is avoided from the mother in cradle.

In some embodiments, the method provides a daily dose of the infant of about 0.3mg or less of triamcinolone acetonide. In some embodiments, the method achieves a relative infant dose of less than about 9% of the subject body weight adjustment dose. In some embodiments, the method achieves a relative infant dose of less than about 5% of the subject body weight adjustment dose.

In some embodiments, the infant does not experience agitation, insomnia, anorexia, or weight gain reduction caused by the thaumatin exposure.

In some embodiments, the subject is 1 day to 24 months post-partum or 10 days to 12 months post-partum (52 weeks).

In some embodiments, the subject is treating narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit/hyperactivity disorder, cognitive impairment, or binge eating disorders with suofurant.

In some embodiments, the subject is a female between 18 and 45 years of age.

In some embodiments, the adverse event is one or more of agitation, insomnia, anorexia, or weight gain reduction.

A method of treating a disorder suitable for treatment with suafrican tray in a subject being breast fed with an infant is provided, the method comprising orally administering to the subject suafrican tray at a daily dose of between about 37.5mg and 300 mg.

These and other aspects of the invention are set forth in more detail in the description of the invention that follows.

Drawings

Figure 1 time course of mean thaumatin breast milk and plasma concentration-time curves on a linear scale and a half-log scale.

Figure 2-average breast milk cumulative suafricant amount-time curve on a linear scale after single dose administration of a 150mg tablet of suafricant.

Detailed Description

The present invention will now be described in more detail with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. In addition, any references cited herein are incorporated by reference in their entirety.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entirety to provide teachings relating to the sentences and/or paragraphs in which the references appear.

Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein may be used in any combination.

Furthermore, the invention also contemplates that, in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

For purposes of illustration, if the specification states that the complex contains components A, B and C, it is specifically intended that either one or a combination of A, B or C may be omitted and abandoned, alone or in any combination.

As used in the description of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in an alternative ("or") manner.

As used herein, the term "about" when referring to a measurable value (such as the amount of polypeptide, dose, time, temperature, enzymatic activity or other biological activity, etc.) is intended to encompass a variation of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

As used herein, the transitional phrase "consisting essentially of and consisting of" (and grammatical variants thereof) should be construed to encompass the recited materials or steps and materials or steps that do not materially affect the basic and novel characteristics of the claimed invention(s). Thus, the first and second substrates are bonded together, the term "substantially as used herein. The composition" should not be interpreted as being equivalent to "comprising.

The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of a composition, compound, or agent of the present invention that imparts a modulating effect on a subject suffering from a disorder, disease, or condition, which modulating effect may be, for example, a beneficial effect, including improving the subject's condition (e.g., one or more symptoms), delaying or reducing disease progression, preventing or delaying the onset of a disorder, and/or altering clinical parameters, diseases, or conditions, and the like, as is well known in the art. For example, a therapeutically effective amount or effective amount may refer to an amount of a composition, compound, or pharmaceutical agent that improves the condition of a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

"Pharmaceutically acceptable carrier" (sometimes referred to as "carrier") refers to a carrier or excipient that can be used to prepare a generally safe and nontoxic pharmaceutical or therapeutic composition, and includes carriers that are acceptable for veterinary and/or human pharmaceutical or therapeutic use. The term "carrier" or "pharmaceutically acceptable carrier" may include, but is not limited to, phosphate buffered saline solution, water, emulsions (such as oil-in-water or water-in-oil emulsions), and/or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as further described herein.

The terms "modulate (modulate)", "modulate (modulates)" or "modulation" refer to enhancing (e.g., increasing) or inhibiting (e.g., decreasing) a specified level or activity.

The term "enhancement" or "increase" refers to at least about a 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold increase in a specified parameter, and/or may be expressed as an enhancement and/or increase of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more of a specified level and/or activity.

As used herein, "inhibit" or "decrease" or grammatical variations thereof refers to a decrease or decrease of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more of a specified level or activity. In certain embodiments, inhibition or reduction results in little or no detectable activity (up to an insignificant amount, e.g., less than about 10% or even 5%).

"Treatment," "treatment," and similar terms as used herein in the context of treating a subject refer to providing medical and/or surgical management of the subject. Treatment may include, but is not limited to, administration of a pharmaceutical agent or composition (e.g., a pharmaceutical composition) to a subject. Treatment is typically performed in order to alter the course of a disease (which term is used to indicate any disease, disorder, syndrome or undesired condition that may or may need treatment) in a manner beneficial to the subject. The effect of treatment may include reversing, alleviating, reducing the severity of, delaying the onset of, curing, inhibiting the progression of, and/or reducing the likelihood of occurrence or recurrence of the disease or one or more symptoms or manifestations of the disease. The therapeutic agent may be administered to a subject suffering from a disease or at increased risk of suffering from a disease relative to a member of the general population. In some embodiments, the therapeutic agent may be administered to a subject who had once had the disease but no longer showed signs of the disease. For example, the agent may be administered to reduce the likelihood of recurrence of the apparent disease. The therapeutic agent may be administered prophylactically, i.e., prior to any symptoms or manifestations of the disease. "prophylactic treatment" refers to providing medical and/or surgical management to a subject who has not had a disease or who has not shown signs of a disease, for example, to reduce the likelihood that a disease will occur, delay the onset of a disease, or reduce the severity of a disease if it occurs. The subject may have been determined to be at risk for developing a disease (e.g., at increased risk relative to the general population), or have a risk factor that increases the likelihood of developing a disease.

The grammatical variations of "administration (administer)", administration (adminisfration) ", and Administration (ADMINISTERING)", to a subject, include any route of introducing or delivering an agent to a subject. Administration may be by any suitable route, including oral, topical, intravenous, subcutaneous, transdermal, intramuscular, intra-articular (intra-joint), parenteral, intra-arteriolar, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implantable reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular (intra-articular), intrasynovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques), and the like. As used herein, "concurrent administration," "combination administration," "simultaneous administration," or "administered simultaneously" refers to administration of compounds at the same point in time, overlapping in time, or one after the other. In the latter case, the two compounds are administered in close enough time that the observed results are indistinguishable from those achieved when the compounds are administered at the same point in time. "systemic administration" refers to the introduction or delivery of an agent to a subject by a route that introduces or delivers the agent to a broad area of the subject's body (e.g., greater than 50% of the body), such as by entering the circulatory system or lymphatic system. In contrast, "topical administration" refers to the introduction or delivery of an agent to a subject by way of introducing or delivering the agent to the area of the point of administration or the area immediately adjacent to the point of administration and without introducing the agent systemically in a therapeutically significant amount. For example, a topically administered agent is readily detectable near the local vicinity of the point of administration, but is not detectable or is detectable in negligible amounts in the distal portion of the subject's body. Administration includes self-administration and administration by others.

As used herein, "pharmaceutically acceptable" refers to materials that are not biologically or otherwise undesirable, i.e., the materials may be administered to an individual with the compositions of the present invention without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which they are contained. The materials should be naturally selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as is well known to those skilled in the art (see, e.g., remington's Pharmaceutical Science; 21 st edition, 2005).

"In parallel" means sufficiently close in time to produce a combined effect (that is, in parallel may be simultaneous, or it may be that two or more events occur within a short period of time before or after each other). In some embodiments, administration of two or more compounds "concurrently" refers to administration of the two compounds sufficiently close in time that the presence of one compound alters the biological effect of the other compound. The two compounds may be administered in the same or different formulations or sequentially. Concurrent administration may be by mixing the compounds prior to administration, or by administering the compounds in two different formulations, e.g., at the same point in time but at different anatomical sites, or using different routes of administration.

As used herein, "bioavailability" refers to the estimated area under the curve or AUC of an active drug in the systemic circulation after oral administration with a dosage form as disclosed herein, as compared to the AUC of the active drug in the systemic circulation after intravenous administration of the active drug. AUC is affected by the extent of absorption of a drug in the Gastrointestinal (GI) tract.

A product is considered "bioequivalent" if the relative average C _max、AUC_(0-t) and AUC _(0-∞) of the test product and the reference product are within 80% to 125%.

The term "AUC _(0-t)" refers to the area under the plasma concentration curve from time 0 to time t.

The term "AUC _(0-∞)" or "AUC _0-inf" refers to the area under the plasma concentration time curve from time 0 to infinity.

"C _max" refers to the maximum milk or plasma concentration of thaumatin.

"T _max" refers to the time for a given drug to reach maximum milk or plasma concentration.

"T _1/2" refers to the time during which milk and plasma concentrations decrease by 50% during the final elimination phase of the drug.

Milk to plasma ratio refers to the AUC in breast milk divided by the AUC in plasma.

"A _Milk" refers to the amount excreted in breast milk within 72 hours.

"Vd/F" refers to the apparent volume of distribution in plasma.

"CL/F" is the apparent oral clearance in plasma.

AUC0-t is the area under the concentration-time curve from time 0 to time t of the last quantifiable concentration (milk and plasma).

By "excessive daytime sleepiness" or "EDS" is meant that an individual is continually sleepy for the time that wakefulness and alertness are expected, even during the daytime after significantly adequate or even prolonged night sleep. EDS may be the result of sleep disorders or a symptom of another potential disorder, such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia. While the designation includes "daytime", it should be appreciated that sleepiness may occur at other times when the subject should wake, such as overnight or at other times, for example, if the subject is working at night. It should also be appreciated that EDS is medically distinct from fatigue and fatigue-related disorders.

The present invention is based in part on the use in a lactating subject suffering from a disorder amenable to treatment with sorafenibA method of (referred to herein as thafenitro (also referred to as (R) -2-amino-3-phenylpropyl carbamate (APC) hydrochloride, and previously referred to as JZP-110, ADX-N05, R228060, and YKP 10A)), while reducing the likelihood of adverse effects in the breast-fed infant of the subject. The thaumatin was FDA approved for administration at doses corresponding to 37.5mg, 75mg and 150mg APC (corresponding to 44.7mg, 89.3mg and 178.5mg APC hydrochloride, respectively). Administration of triamcinolone acetonide to breast milk expressing subjects presents challenges. In a non-clinical study performed on rats, thaumatin was detected in breast milk, while thaumatin milk concentration was higher than thaumatin plasma concentration. It is desirable to reduce or minimize any adverse effects caused by daily doses received by breast-fed infants from subjects treated with suofatuo. Additionally, it is desirable to determine a method that allows for the safety and tolerability of suofatuo in a mammalian subject.

Accordingly, one aspect of the invention relates to a method of reducing exposure to coaptan in a breast-fed infant obtained from a subject treated with coaptan, comprising orally administering coaptan to the subject at a daily dose of about 37.5mg to about 300mg, and feeding breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after coaptan is administered to the subject to the infant, thereby reducing exposure to coaptan in the infant.

One aspect of the invention includes a method for reducing the likelihood of an adverse event caused by suafrican tray in a breast-fed infant obtained from a subject treated with suafrican tray, comprising orally administering to the subject suafrican tray at a daily dose of between 37.5mg and 300mg, and feeding to the infant breast milk from the subject at least about 2 hours (e.g., at least about 3,4, or 5 hours) after administration of the suafrican tray to the subject, thereby reducing the likelihood of an adverse event caused by suafrican tray in the infant. In one embodiment, the adverse event is one or more of agitation, insomnia, anorexia, or weight gain reduction.

Another aspect of the invention relates to a method of avoiding exposure of an infant of a nursing mother being treated with sorafenib to peak concentrations of cord An Feituo excreted in breast milk, such method comprising not feeding to the infant breast milk obtained within at least about 3.5 hours (e.g., within at least about 4 or 5 hours) of the mother receiving a once daily oral dose of sorafenib, wherein the median T _max excreted in the breast milk is about 1.1 hours. In clinical studies, T _max ranged from 1 hour to 3 hours. Thus, waiting at least 3.5 hours after administration of the triamcinolone acetonide ensures avoidance of T _max even for abnormal subjects.

A further aspect of the invention relates to a method of reducing the exposure of a baby receiving breast milk from a nursing mother to thaumatin from breast milk, the nursing mother being treated with a daily single dose of about 37.5mg to about 300mg of thaumatin to treat a disorder suitable for treatment with thaumatin, such method comprising feeding the baby with breast milk obtained from the mother at least about 5 hours (e.g., at least 6, 7, 8, 9 or 10 hours) after administration of thaumatin to the mother, wherein the baby's exposure to thaumatin is reduced by at least about 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%) as compared to the exposure to the baby that would result from breast milk obtained from the mother less than 5 hours after administration of thaumatin. In some embodiments, the resulting relative infant dose is about 2% or less of the maternal weight adjustment dose. In some embodiments, the once daily dose of the thaumatin is 150mg and the daily amount of the thaumatin delivered to the infant by breast milk is about 0.3mg or less. In some embodiments, the once daily dose of the thaumatin is 75mg and the daily amount of the thaumatin delivered to the infant by breast milk is about 0.15mg or less. In some embodiments, breast milk is obtained from the mother at least about 10 hours (e.g., about 2 half-lives) after administration of the thaumatin to the mother, and the infant's exposure to the thaumatin is reduced by at least about 75% compared to the exposure that would result from feeding the infant with breast milk obtained from the mother less than 5 hours after administration of the thaumatin. In some embodiments, the resulting relative infant dose is about 1% or less of the maternal weight adjustment dose.

One aspect of the invention relates to a method for treating a disorder treatable with suafrican tray in a subject producing breast milk for feeding an infant, comprising orally administering to the subject suafrican tray at a daily dose of between 37.5mg and 300mg, and reducing exposure to suafrican tray and/or reducing the likelihood of adverse events in a breast-fed infant from the subject, comprising feeding to the infant breast milk obtained from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administration of suafrican tray to the subject. In one embodiment, the method reduces the amount of triamcinolone acetonide in the infant and the infant does not experience agitation, insomnia, anorexia, or weight gain reduction caused by the exposure of triamcinolone acetonide. In one embodiment, the adverse event is one or more of agitation, insomnia, anorexia, or weight gain reduction.

"Disorder suitable for treatment with suafricant" or "disorder treatable with suafricant" refers to any disorder in which administration of suafricant to a subject results in treatment of one or more symptoms of the disorder in the subject. Examples of disorders suitable for treatment with suofatuo include narcolepsy, cataplexy, excessive daytime sleepiness, obstructive sleep apnea, shift work disorders, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention Deficit Hyperactivity Disorder (ADHD), cognitive impairment and/or cognitive dysfunction, parkinson's disease, restless leg syndrome, depression, bipolar disorder, obesity, or binge eating disorders. In some embodiments, the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or parkinson's disease. In some embodiments, the disorder suitable for treatment with suofatuo includes narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit/hyperactivity disorder, or binge eating disorder. In some embodiments, the suofatuo is administered to improve wakefulness. See, for example, U.S. patent nos. 8,232,315, 8,440,715, 8,552,060, 8,623,913, 8,729,120, 8,741,950, 8,895,609, 8,927,602, 9,226,910, and 9,359,290, and U.S. publication nos. 2012/0004300 and 2015/0018414. All of the above patents and applications are incorporated herein by reference in their entirety for all purposes.

In some embodiments, the cause of EDS may be, but is not limited to, pathological abnormalities of the Central Nervous System (CNS), stroke, narcolepsy, idiopathic CNS hypersomnia, sleep deficiency, sleep apnea, obstructive sleep apnea, nocturnal sleep insufficiency, chronic pain, acute pain, parkinson's disease, urinary incontinence, multiple sclerosis fatigue, attention Deficit Hyperactivity Disorder (ADHD), alzheimer's disease, major depression, bipolar disorder, myocardial ischemia, disorders of the human circadian pacemaker and environment, jet lag, shift work disorder, or sedative medication.

In certain embodiments, the structure of the sorafenib is given below as formula I:

Methods for preparing suafiton and related compounds can be found in U.S. patent nos. 10,829,443, 5,955,499, 5,705,640, 6,140,532, and 5,756,817. All of the above patents and applications are incorporated herein by reference in their entirety for all purposes.

In one embodiment, the methods detailed herein provide that breast-fed infants from subjects to whom the sorafenib are administered do not experience adverse events, such as agitation, insomnia, anorexia, or weight gain reduction caused by the sorafenib exposure. Agitation, insomnia, anorexia, or weight gain reduction in infants can be monitored. For example, weight loss, weight gain reduction, reduced feeding frequency or reduced intake, reduced milk intake volume may be monitored and/or detected. An increase in agitation and/or insomnia of the infant, including a decrease in sleep time and/or a decrease in the time to fall asleep and stay asleep, may also be monitored to determine changes in the infant. In some embodiments, the change in the infant is monitored 3 hours or more after administration of the suofatuop dose and after starting feeding the infant with breast milk from the subject, e.g., 3 hours, 4, hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours or more after administration of the suofatuop dose. Any changes (e.g., agitation, insomnia, anorexia, or weight gain reduction) experienced by the infant may be monitored over a period of time that the subject is administered to the suofatuo, which may be within days, weeks, or months, wherein monitoring is over any time interval within the period of time, including hourly, daily, weekly, monthly, or any time range therein.

In one embodiment, the method provides a daily dose of about 0.4mg or less of the infant of thanot, e.g., about 0.39mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.335mg, about 0.33mg, about 0.32mg, about 0.21mg, about 0.30mg, about 0.29mg, about 0.28mg, about 0.27mg, about 0.26mg, about 0.25mg, about 0.24mg, about 0.23mg, about 0.22mg, about 0.21mg, about 0.20mg, about 0.19mg, about 0.18mg, about 0.17mg, about 0.16mg, about 0.15mg, about 0.14mg, about 0.13mg, about 0.12mg, about 0.11mg, about 0.10mg, about 0.09mg, about 0.08mg, about 0.07mg, about 0.06mg, about 0.03mg, about 0.02mg, or less than about 0.03 mg. The daily dosage for an infant refers to the daily dosage that the infant receives by breast feeding. In some embodiments, a once daily dose of about 150mg of suofacitor is orally administered to the subject, and the daily dose of the infant of suofacitor is reduced to about 0.3mg or less due to the waiting period following administration. In some embodiments, a once daily dose of about 75mg of suofacitor is orally administered to the subject, and the daily dose of the infant of suofacitor is reduced to about 0.15mg or less due to the waiting period following administration. In some embodiments, a once daily dose of about 37.5mg of the sorafenib is orally administered to the subject, and the daily dose of the infant of the sorafenib is reduced to about 0.08mg or less due to the waiting period following administration.

In one embodiment, the method provides a daily dosage of about 0.2mg/kg (based on a nominal infant weight of 6 kg) or less of the infant of thanot-tuin, e.g., about 0.19mg/kg, about 0.18mg/kg, about 0.17mg/kg, about 0.16mg/kg, about 0.15mg/kg, about 0.14mg/kg, about 0.13mg/kg, about 0.12mg/kg, about 0.11mg/kg, about 0.10mg/kg, about 0.09mg/kg, about 0.08mg/kg, about 0.07mg/kg, about 0.06mg/kg, about 0.05mg/kg, about 0.04mg/kg, about 0.03mg/kg, about 0.02mg/kg, about 0.01mg/kg or less.

In one embodiment, the method provides an accumulated median infant dose of the thaumatin that is about 0.7mg or less within 72 hours after a single dose, e.g., about 0.69mg, about 0.68mg, about 0.67mg, about 0.66mg, about 0.65mg, about 0.64mg, about 0.63mg, about 0.62mg, about 0.61mg, about 0.60mg, about 0.59mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg, about 0.41mg, about 0.40mg, about 0.39mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.355mg, about 0.33mg, about 0.32mg, about 0.31mg, about 0.27mg, about 0.24mg, about 0.18mg, about 0.15mg, about 0.30mg, about 0.14mg, about 0.30mg, about 0.18mg, about 0.13mg, about 0.15mg, about 0.12mg, about 0.13mg, about 0.14mg, about 0.13mg, about 0.26mg, about 0.13 mg.

In some embodiments, the method provides a cumulative median infant dose of the thaumatin after a single dose of about 75% -80%, e.g., about 75%, 76%, 77%, 78%, 79% or 80% of the total excreted in 72 hours after 8 hours. In some embodiments, the method provides a cumulative median infant dose of the thaumatin after 24 hours of total excretion of about 95% -100%, e.g., about 95%, 96%, 97%, 98%, 99% or 100%, of the total excretion within 72 hours after a single dose.

In some embodiments, breast milk for feeding an infant is expressed or produced from the subject 2 or more hours, 2.5 or more hours, 3 or more hours, 3.5 or more hours, 4 or more hours, 4.5 or more hours, or 5 or more hours, e.g., at 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours or more after administration of the suafungin dose to the subject. In some embodiments, breast milk produced from a subject for infant feeding in the methods detailed herein occurs at about the mean elimination half-life of the thaumatin or later, i.e., about 5 hours after administration of the thaumatin. In some embodiments, breast milk produced from a subject for infant feeding in the methods detailed herein occurs about 2-4 times or later than the median T _max of the thaumatin, i.e., about 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours after administration of the thaumatin. In some embodiments, breast feeding of the infant occurs 3 or more hours, 4 or more hours, or 5 or more hours after administration of the suafricant dose to the subject. In some embodiments, breast milk for feeding an infant is obtained from the subject 3 or more hours, 4 or more hours, or 5 or more hours after administration of the suafricant dose to the subject.

In some embodiments, the subject does not breast-feed the infant during a waiting period (e.g., 2 or more hours). In other embodiments, breast milk produced during the waiting period is expressed and not fed to the infant, e.g., wherein the expressed breast milk is discarded.

In some embodiments, the method achieves a weight adjustment dose of less than about 10%, less than about 9.5%, less than about 9%, less than about 8.5%, less than about 8%, less than about 7.5%, less than about 7%, less than about 6.5%, less than about 6%, less than about 5.5%, less than about 4.9%, less than about 4.8%, less than about 4.7%, less than about 4.6%, less than about 4.5%, less than about 4.4%, less than about 4.3%, less than about 4.2%, less than about 4.1%, less than about 4.0%, less than about 3.9%, less than about 3.8%, less than about 3.7%, less than about 3.6%, less than about 3.5%, less than about 3.4%, less than about 3.2%, less than about 3.0%, less than about 2.9%, less than about 2.8%, less than about 2.7%, less than about 1.1%, less than about 2.1%, less than about 1% of the subject's body weight.

In some embodiments of the present invention, in some embodiments, the cumulative median amount of cable non-torr delivered to a breast-fed infant over 72 hours produced by a subject treated with cable non-torr in accordance with the methods disclosed herein is less than about 0.70mg, about 0.69mg, about 0.68mg, about 0.67mg, about 0.66mg, about 0.65mg, about 0.64mg, about 0.63mg, about 0.62mg, about 0.61mg, about 0.60mg, about 0.59mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg about 0.41mg, about 0.40mg, about 0.39mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.335mg, about 0.33mg, about 0.32mg, about 0.31mg, about 0.30mg, about 0.29mg, about 0.28mg, about 0.27mg, about 0.26mg, about 0.25mg, about 0.24mg, about 0.23mg, about 0.22mg, about 0.21mg, about 0.20mg, about 0.19mg, about 0.18mg, about 0.17mg, about 0.16mg, about 0.15mg, about 0.14mg, about 0.13mg, about 0.12mg, about 0.11mg, about 0.10mg, about 0.09mg, about 0.08mg, about 0.07mg, about 0.06mg, about 0.05mg, about 0.04mg, about 0.03mg, about 0.02mg, or about 0.02 mg.

In some embodiments of the present invention, in some embodiments, the cumulative median amount of cable non-torr delivered to breast-fed infants over 24 hours produced by a subject treated with cable non-torr in accordance with the methods disclosed herein is less than about 0.70mg, about 0.69mg, about 0.68mg, about 0.67mg, about 0.66mg, about 0.65mg, about 0.64mg, about 0.63mg, about 0.62mg, about 0.61mg, about 0.60mg, about 0.59mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg about 0.41mg, about 0.40mg, about 0.39mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.33mg, about 0.32mg, about 0.31mg, about 0.30mg, about 0.29mg, about 0.28mg, about 0.27mg, about 0.26mg, about 0.25mg, about 0.24mg, about 0.23mg, about 0.22mg, about 0.21mg, about 0.20mg, about 0.19mg, about 0.18mg, about 0.17mg, about 0.16mg, about 0.15mg, about 0.14mg, about 0.13mg, about 0.12mg, about 0.11mg, about 0.10mg, about 0.09mg, about 0.08mg, about 0.07mg, about 0.06mg, about 0.05mg, about 0.04mg, about 0.03mg, about 0.02mg or about 0.01mg.

In some embodiments of the present invention, in some embodiments, the cumulative median amount of cable non-torr delivered to breast-fed infants produced by a subject treated with cable non-torr in accordance with the methods disclosed herein over 8 hours is less than about 0.70mg, about 0.69mg, about 0.68mg, about 0.67mg, about 0.66mg, about 0.65mg, about 0.64mg, about 0.63mg, about 0.62mg, about 0.61mg, about 0.60mg, about 0.59mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg about 0.41mg, about 0.40mg, about 0.39mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.33mg, about 0.32mg, about 0.31mg, about 0.30mg, about 0.29mg, about 0.28mg, about 0.27mg, about 0.26mg, about 0.25mg, about 0.24mg, about 0.23mg, about 0.22mg, about 0.21mg, about 0.20mg, about 0.19mg, about 0.18mg, about 0.17mg, about 0.16mg, about 0.15mg, about 0.14mg, about 0.13mg, about 0.12mg, about 0.11mg, about 0.10mg, about 0.09mg, about 0.08mg, about 0.07mg, about 0.06mg, about 0.05mg, about 0.04mg, about 0.03mg, about 0.02mg or about 0.01mg.

Daily doses of about 1 to about 2000mg of triamcinolone acetonide, or a pharmaceutically acceptable salt thereof, may be administered to achieve the therapeutic results disclosed herein. For example, a daily dose of about 1-1000mg (e.g., about 20-500 mg) is administered in a single dose or in divided doses. In some embodiments, the daily dose may be about 0.01 to about 150mg/kg body weight, for example, about 0.2 to about 18mg/kg body weight. In some embodiments, the dose contains about 1mg to about 1000mg of the drug or any range or value therein, e.g., about 10mg to about 500mg, e.g., about 37.5mg, about 75mg, about 150mg, or about 300mg. For example, in certain such embodiments, the total amount of drug may be selected from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, or any range therein.

In one embodiment of the invention, the subject is administered triamcinolone acetonide as needed to treat the disorder. The compound may be administered continuously or intermittently. In one embodiment, the compound is administered to the subject more than once daily, e.g., 2,3, or 4 times daily, or once every 1,2,3, 4,5, 6, or 7 days. In another embodiment, the compound is administered to the subject no more than once a week, e.g., no more than once every two weeks, once every month, once every two months, once every three months, once every four months, once every five months, once every six months, or longer. In further embodiments, two or more different schedules are used to administer the compound, e.g., initially more frequently (e.g., gradually increasing to a certain level, e.g., once a day or more), and then less frequently (e.g., once a week or less). In other embodiments, the compound may be administered by any discontinuous administration regimen. In one example, the compound may be administered no more than once every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days, or every ten days or more. The administration may last one week, two weeks, three weeks or four weeks or one month, two months or three months or more. Optionally, after a period of rest, the compounds may be administered according to the same or different schedule. The period of rest may be one week, two weeks, three weeks or four weeks or longer, depending on the pharmacodynamic effect of the compound on the subject. In another embodiment, the compound may be administered to gradually increase to a certain level, then maintained at a constant level, and then gradually decrease in dose.

In one aspect of the invention, the triamcinolone acetonide is delivered to the subject concurrently with the additional therapeutic agent. The additional therapeutic agent may be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent may be delivered to the subject on a different schedule or by a different route than the compound. The additional therapeutic agent may be any agent that provides a benefit to the subject. Additional agents include, but are not limited to, stimulants, antipsychotics, antidepressants, agents for neurological disorders, and chemotherapeutic agents. One therapeutic agent that may be administered during the same period of time isCommercially available from Jazz Pharmaceuticals for use in the treatment of narcolepsy and cataplexy. See U.S. patent nos. 8,952,062 and 9,050,302.

The invention is useful in research, veterinary and medical applications. Suitable subjects are typically mammalian subjects. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and the like. Human subjects include neonates, infants, adolescents, adults and geriatric subjects. In some embodiments, the subject is a post-partum subject. In some embodiments, the subject is a female between 18 and 45 years of age.

Suitable subjects are typically mammalian subjects in the lactation period. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, cows, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), and the like. The human subject may be a lactating individual who regularly or regularly breastfeeds an infant. In some embodiments, the human subject is a female. The female may be between about 18 and 45 years of age. The term "breast feeding" (which may also be referred to as breast feeding or grammatical variations thereof) refers to the delivery of an individual's breast milk directly to an infant, the use of a device to extract breast milk from an individual and subsequently to the infant, the use of a device to extract breast milk from an individual and store the breast milk for a period of time and subsequently deliver the stored breast milk to the infant, or a combination thereof.

The subject of the present disclosure may be in a lactation period, e.g., an individual who is lactation (e.g., producing breast milk), lactation, or breast feeding. The subject may be in lactation after gestation (i.e., post-partum) or by induced lactation (e.g., with metoclopramide, oral contraceptives, herbal medicines, by pumping stimulation, or any combination thereof).

In some embodiments, the subject is between 1 day and 24 months post-partum, between about 1 day and 12 months post-partum, between about 10 days and 12 months post-partum (52 weeks), or between about 15 weeks post-partum and about 37 weeks post-partum. In some embodiments, the subject expresses mature milk, which typically occurs about 10 to about 30 days post-partum (e.g., about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days), or about 10 to about 20 days post-partum, or about 10 to about 20 days after expression of milk begins in induced lactation. The infancy starts at birth and ends around the age of 2 years, and thus the period of the infant being breast fed includes the breast feeding period.

The subject may be a subject "in need of" the methods of the invention, e.g., a subject in need of the therapeutic effects of the methods of the invention. For example, the subject may be a subject experiencing a disorder suitable for treatment with suafrican, a subject suspected of experiencing a disorder suitable for treatment with suafrican, and/or a subject expected to experience a disorder suitable for treatment with suafrican, and the methods and compositions of the present invention are useful for therapeutic and/or prophylactic treatment.

In some embodiments, the subject is a mother whose disease or disorder places her infant at risk of an adverse event that occurs as a result of a maternal condition (e.g., she sleeps while taking care of the infant), and who wishes to breast feed. Surveys show that at least 60% of women with narcolepsy report difficulty in caring for their infants due to their symptoms and fear of being impaired by their illness in relation to caring for their infants.

Accordingly, one aspect of the invention relates to a method of treating excessive daytime sleepiness in a nursing mother, whose infant is at risk of adverse events caused by excessive daytime sleepiness in the mother, and which desires to breast-feed the infant, comprising (a) determining whether a total score of Ai Puwo s sleepiness scale (ESS) of the mother and the mother experience sleep onset while taking care of the infant, (b) providing to the mother having a total score of ESS of 15 or more and experiencing sleep onset while taking care of the infant, a starting dose of 37.5mg once daily (if excessive daytime sleepiness is associated with obstructive sleep apnea) or 75mg once daily (if excessive daytime sleepiness is associated with narcolepsy) and multiplying the dose at least 3 day intervals up to 150mg once daily, wherein the elimination half-life of suofnon-cradle in the plasma of the mother is about 5 hours, and (c) providing to the infant a maximum of breast-cradle-milk concentration of 531 from the mother is avoided in the infant at least about 5 hours after administration of suofcradle-cradle-time to the infant, wherein the maximum cradle-time is breast-milk-cradle-1 is avoided.

The method selects a subject suitable for treatment based on the severity of the disease, the disturbance of infant care, and the desire of the mother to provide breast-fed development and health benefits to the infant.

ESS is a subjective sleepiness test well known in the art and is routinely used to measure the level of sleepiness in a subject. The scale is intended to measure daytime sleepiness by using a short questionnaire that requires the subject to rate his or her probability of falling asleep on an ascending probability scale from 0 to 3 of eight different situations most people encounter in their daily lives. The scores of the eight questions are added together to obtain a single number that estimates the average sleep tendency (ASP) of the subject. Numbers in the range of 0-10 are considered normal, while 11-12 indicate light excessive sleepiness, 13-15 indicate moderate excessive sleepiness, and 16 or higher indicate severe excessive sleepiness. The narcolepsy patient had an average score of about 17. Patients with Obstructive Sleep Apnea (OSA) with excessive sleepiness have an average score of about 15.

As used herein, a "sleep episode" refers to a strong sleep impulse, typically followed by a period of sleep time in which there is no control over when to fall asleep. These time periods may last from a few seconds to half an hour.

In some embodiments, the nursing mother experiences a decrease in total score of ESS of 5 or more (e.g., 6, 7, 8, 9, or 10 or more).

In some embodiments, the nursing mother experiences a decrease in the frequency of sleep episodes while holding, feeding, nursing, or otherwise caring for the infant. The reduction in frequency may be at least about 10%, 20%, 30%, 40% or 50% compared to untreated mother.

In some embodiments, the nursing mother experiences a reduction in automated movement (movement of a body part, such as movement of his hands while sleeping) while taking care of the infant. The reduction in automated movement may be at least about 10%, 20%, 30%, 40% or 50% compared to untreated mother.

Having described the invention, the invention will be explained in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

Examples

Example 1 phase 4 clinical trial in Breast-fed subjects

A single dose study of phase 4 open label to evaluate the Pharmacokinetics (PK) of suafrican tols in breast milk and plasma after oral administration of 150mg of a tablet of suafrican tols in healthy postnatal women.

The study was conducted in 6 healthy adult lactating women 15 to 37 weeks post partum and administered a single oral dose of SUNOSI mg. SUNOSI is excreted in breast milk, the AUC ratio of milk to plasma is about 2:1.SUNOSI the median T _max in breast milk is about 1.1 hours and the average elimination half-life in breast milk is about 5.0 hours. The average amount delivered to the infant over 24 hours was estimated to be 0.59mg, which is about 4.0% of the parent dose by weight adjustment. Data from lactating studies indicate that SUNOSI is transferred to the breast milk of a lactating mother, with a Relative Infant Dose (RID) of about 4% of the maternal weight adjustment dose. No data is provided to evaluate the effect SUNOSI on breast-fed infants or milk production. The developmental and health benefits of breast feeding should be considered, as well as the clinical needs of the mother on SUNOSI, and any potential adverse effects of SUNOSI or potential maternal conditions on breast fed children. Adverse effects such as agitation, insomnia, anorexia and weight gain reduction in breast-fed infants should be monitored.

The thaumatin has a short systemic elimination half-life of 5.0 to 7.6 hours and an estimated accumulation rate of 1.06 with once daily dosing, slightly above 1, indicating substantially no accumulation with repeated dosing. Thus, a single therapeutic dose of suofacitor was administered in this study. Since the objective of this study was to evaluate the thaumatin PK in breast milk and plasma, and to estimate the daily drug dose that infants received from breast milk, the highest approved therapeutic dose of 150mg thaumatin was administered.

The subject is between 10 days and 52 weeks postnatal. The lower time limit of 10 days post partum represents the time after which mature milk is produced (U.S. FDA 2019). The upper time limit of 52 weeks post-partum was chosen based on a prospective study showing that fat, total solids, and "energy" (kcal/dL) were all statistically increased in breast milk collected from 12 to 18 months post-partum (n=25) compared to breast milk collected from 1 to 12 months post-partum (Czosnykowska Lukacka 2018). In addition, little data is available on the nutritional composition of breast milk for >12 months post partum (Wu 2018). The study included frequent collection of breast milk samples during the 72 hour period following dosing to enable detection of possible presence of thaumatin in breast milk. Plasma concentrations of thaumatin were also evaluated during the same time period to assess potential accumulation of thaumatin in breast milk relative to plasma.

The subject was instructed not to breast feed his infant for 72 hours after the dose. Based on the short half-life of the drug, this period (10 x half-life) is expected to be of sufficient duration to completely eliminate the sorafenib from both the systemic circulation and breast milk.

Pharmacokinetic results

All subjects in the PK population were included in the PK analysis. A pharmacokinetic population is defined as all subjects receiving a study drug and providing post-dose breast milk or plasma PK data for at least one collection time interval or time point. Subjects 1003, 1004 and 1007 had multiple recorded protocol deviations in terms of food consumption time, but these deviations were unlikely to affect the sorafenib PK, and these subjects were included in descriptive statistics or PK parameter analysis. In addition, PK of solanfolt in fed and fasted subjects met bioequivalence criteria, indicating that solanfolt can be taken regardless of food intake.

Mean plasma and breast milk suafocal concentration time curves are shown in fig. 1. Figure 1 shows the time course of balance 1 mean plasma and breast milk suafrican concentrations after a single dose administration of a 150mg tablet of suafrican at 2 hours after completion of the light breakfast in the morning. Plasma and breast milk exposure followed a parallel single exponential drop after reaching the maximum suoamphetamine concentration approximately 1.00 to 3.00 hours after oral administration. The concentration of suafocal in breast milk is about 2 times higher than the plasma concentration.

The average breast milk cumulative suafrican told-time curve is shown in fig. 2. Figure 2 shows the average breast milk cumulative suafrican told-time curve after a single dose administration of a 150mg tablet of suafrican told 2 hours after completion of a light breakfast in the morning. The arithmetic mean.+ -. SD amount excreted in breast milk within 72 hours was 0.6880.+ -. 0.4672mg. But almost complete excretion was observed within 24 hours of administration.

No subjects had a Rsq adjustment <0.700 or% AUCex >20% and thus both λ_z and AUC0-inf related parameters were considered reliable and included in descriptive statistics.

Table 1 summarizes the plasma and breast milk PK parameters of suafricant after a single dose administration.

The mean of the exposure of suafrican to breast milk was about 2-fold higher than the exposure to plasma, the geometric mean C _max was 1861 relative to 892.5ng/mL, AUC _0-t was 12770 relative to 6236h ng/mL, and AUC _0-inf was 12940 relative to 6340h ng/mL, respectively. The geometric mean milk to plasma ratio was 2.047.

Plasma suafrican t _max (from 0.98 to 3.02 hours, median 1.25 hours) is similar to breast milk (from 1.00 to 3.00 hours, median 1.12 hours).

The geometric mean thaumatin t _1/2 between plasma (4.751 hours) and breast milk (4.869 hours) looks similar. In addition, the geometric mean plasma Sofosol CL/F is 23.66L/h and V _z/F is 162.2L. Geometric mean A _Milk was 0.5651mg, and daily and relative infant doses were 0.5856mg and 4.030%, respectively.

TABLE 1 summary of pharmacokinetic parameters of Sorafoxanthode in plasma and Breast milk (pharmacokinetic population)

Nc=not calculated.

Note that CV% is based on arithmetic mean.

^[a] Median (min, max).

Conclusion of pharmacokinetics

The thaumatin-t _max is similar for both plasma and breast milk and ranges between 1 and 3 hours. After the maximum suoanfolt concentration was reached, plasma and breast milk exposure followed a parallel single exponential drop. The thaumatin breast milk exposure (C _max and AUC) was 2 times higher than plasma. In addition, the geometric mean milk to plasma ratio was 2.047. The thaumatin-t _1/2 in plasma and breast milk appeared similar, being about 5 hours. The study is specific to postpartum women and is currentThis is a very different population compared to the population of studies reported in the pharmacokinetic part of the tag (which are non-post-partum healthy male and female patients).The label reports that the oral bioavailability of suafrican tols under fasted conditions in non-postpartum healthy male and female patients is about 95% with the peak plasma concentration of the cable An Feituo occurring at the median T _max (range 1.25 to 3.0 hours) 2 hours post dose. In fact, while the median T _max reported in the label was 2 hours for non-post-partum healthy male and female patients, T _max in the present lactation study was 1 hour. Similarly, for the case of the followingThe apparent mean plasma elimination half-life for non-post partum healthy male and female patients on the label was 7.1 hours, compared to 4.8 hours in plasma and 4.95 hours in breast milk in the present lactation study.

CL/F and V _z/F were determined only for plasma suafricant. The arithmetic mean of CL/F is 24.40L/h and V _z/F is 168.9L. A _Milk, infant daily dose, and relative infant dose were determined for breast milk suoanfolt only. The arithmetic mean of A _Milk was 0.6880mg, the daily infant dose was 0.6927mg, and the relative infant dose was 4.602%.

Security results

Adverse events the overall summary of adverse events (TEAE) occurring in the treatment is summarized in table 2. A total of 3 (50%) subjects had at least 1 AE, a total of 2 (33.3%) subjects had TEAE associated with the study drug, and 1 (16.7%) subjects had TEAE not associated with the study drug. Mild TEAE was reported in 2 (33.3%) subjects and moderate TEAE was reported in 1 (16.7%) subjects. SAE were not reported in the study. No subjects were discontinued by TEAE.

TABLE 2 general summary of adverse events occurring in treatment (safety population)

AE = adverse event, N = number of subjects exposed, SAE = serious adverse event.

Note that the percentages are based on N

A subjects reporting adverse events of more than one category only count for that category.

Of the 3 subjects reporting TEAE, 1 subject had dizziness and headache (SOC: neurological disorder), 1 subject had agitation (SOC: mental disorder), and 1 subject had headache event (SOC: neurological disorder) (table 3). A total of 4 TEAEs were reported, of which 3 TEAEs (dizziness, headache and agitation) were mild in intensity and 1 TEAE (headache) was moderate in intensity. All 3 mild TEAEs were associated with study drug and moderate TEAEs were not associated with study drug. All TEAEs were resolved.

TABLE 3 summary of adverse events occurring in treatment by systemic organ category, preferred terminology (safety population)

N = number of subjects exposed.

Note that the percentages are based on N.

Subjects with multiple adverse events within the major system organ category were counted only once.

Subjects with multiple AE were counted only once in the AE category

Alphabetically presenting the system organ category and alphabetically presenting the preferred terms within the system organ category encodes the adverse event using the MedDRA encoding dictionary MedDRA180 Mixed.

Vital sign from baseline to day 1, 2 hours and 4 hours, day 2, day 3 and day 4, without significant changes in vital sign parameters. A summary of clinically significant vital signs at any post-baseline visit is summarized in table 4.

TABLE 4 summary of clinically significant vital signs at any post-baseline visit/time point (safety population)

N = number of subjects exposed.

Note that the percentages are based on N.

Baseline was defined as the last non-missing measurement performed prior to dosing. All post-baseline evaluations (including unplanned evaluations) were considered for this summary.

There were no significant changes in ECG parameters from baseline to day 1 pre-dose and 2 hours, day 2, day 3 and day 4. No clinically significant ECG findings of abnormalities were reported.

A summary of clinically significant ECG findings at any post-baseline visit is summarized in table 5.

TABLE 5 summary of clinically significant electrocardiograms at any post-baseline visit/time point (safety population)

N = number of subjects exposed.

Note that the percentages are based on N.

According to the Columbia suicide evaluation classification algorithm (Columbia-Classification Algorithm for Suicide Assessment), none of the subjects reported any suicide concept or event.

Conclusion of safety

Overall, 6 subjects were enrolled in a group safety assay and treated with a single oral dose of suofatuo, which was safe and well tolerated.

Of the 6 subjects, 3 (50%) subjects had at least 1 AE. Of the 3 subjects reporting TEAE, 1 subject had dizziness and headache (SOC: neurological disorder) both of mild intensity and associated with study drug, 1 subject had agitation of mild intensity (SOC: mental disorder) and associated with study drug, and 1 subject had headache event of moderate intensity (SOC: neurological disorder) and not associated with study drug. SAE, death or other significant AEs were not reported in the study. All subjects were not discontinued by TEAE. All subjects had no abnormal, clinically significant laboratory findings. There were no significant changes in vital signs from baseline to day 1,2 hours and 4 hours, day 2, day 3 and 4, and no significant changes in ECG parameters from baseline to day 1, pre-dose and 2 hours, day 2, day 3 and 4. According to the columbia suicide evaluation classification algorithm, none of the subjects reported any suicide concept or event.

Discussion of the invention

The study was a phase 4 open label single dose study to evaluate the PK of healthy postnatal women in breast milk and plasma following oral administration of 150mg of the solanfiton tablet. A total of 6 subjects were enrolled in the group and included in both PK and safety analysis. All 6 subjects have completed the study. No premature interruption was reported in the study.

The main objective (PK) of this study was to evaluate the PK of solanfolt in plasma and breast milk after a single oral dose of 150mg tablet of solanfolt 2 hours after completion of the light breakfast in the morning. The mean of the exposure of suafrican to breast milk was about 2-fold higher than the exposure to plasma, the geometric mean C _max was 1861 relative to 892.5ng/mL, AUC _0-t was 12770 relative to 6236h ng/mL, and AUC _0-inf was 12940 relative to 6340h ng/mL, respectively. The geometric mean milk to plasma ratio was 2.047. Plasma suafrican t _max (from 0.98 to 3.02h, median 1.25 h) is similar to breast milk (from 1.00 to 3.00 hours, median 1.12 hours). The geometric mean thaumatin t _1/2 between plasma (4.751 hours) and breast milk (4.869 hours) looks similar. In addition, the geometric mean plasma Sofosol CL/F is 23.66L/h and V _z/F is 162.2L. Geometric mean A _Milk was 0.5651mg, and daily and relative infant doses were 0.5856mg and 4.030%, respectively.

A secondary objective of the study was to evaluate the safety and tolerability of suofacitor in healthy postnatal women. Overall, the study drug was safe and well tolerated. SAE, death or other significant AEs were not reported in the study. All subjects were not discontinued by TEAE. Of the 6 subjects, 3 reported adverse events. All AEs (dizziness, headache and agitation) were mild intensity except 1 AE (headache) for moderate intensity.

All subjects had no abnormal or clinically significant laboratory findings. There were no significant changes in vital signs from baseline to day 1,2 hours and 4 hours, day 2, day 3 and 4, and no significant changes in ECG parameters from baseline to day 1, pre-dose and 2 hours, day 2, day 3 and 4. According to the columbia suicide evaluation classification algorithm, none of the subjects reported any suicide concept or event.

Conclusion(s)

The thaumatin T _max is similar for both plasma and breast milk and ranges between 1 and 3 hours. After the maximum suoanfolt concentration was reached, plasma and breast milk exposure followed a parallel single exponential drop. Thaumatin breast milk exposure (C _max, AUC) was 2-fold higher than plasma. In addition, the geometric mean milk to plasma ratio was 2.047. The thaumatin-t _1/2 in plasma and breast milk appeared similar, being about 5 hours. The triamcinolone acetonide is safe and well tolerated.

Further analysis of the data indicated that the daily infant dose was 0.112mg/kg (based on 6kg nominal infant weight) and the Relative Infant Dose (RID) was about 5.5% of the maternal weight adjusted dose. The data is insufficient to determine the effect of thaumatin on breast-fed infants or its effect on milk production.

The cumulative median excretion in breast milk over 72 hours was 0.67mg, which was about 5.5% of the maternal dose by weight adjustment. Of the total amount of thaumatin excreted in breast milk within 72 hours, approximately 78% and 98% were excreted before 8 and 24 hours, respectively, with an apparent average elimination half-life in breast milk of about 5 hours.

The developmental and health benefits of breast feeding should be considered, as well as the clinical need for coanda by the mother, and any potential adverse effects of coanda or potential maternal conditions on breast fed infants.

Infants exposed to suofatuo should be monitored for signs of agitation, insomnia and weight gain reduction.

Method of

On day-1, eligible subjects underwent a baseline procedure. On day 1,2 hours after the bland breakfast, subjects received a single dose of 150mg of triamcinolone acetonide and 240mL of water. The subjects must be fasted for about 4 hours after the first dose and allowed to drink water in addition to 1 hour before and 1 hour after administration of the study drug.

Pharmacokinetic analysis of breast milk obtained from both breasts (by pumping) was evaluated prior to dose administration and at various time intervals up to 72 hours after dose administration. Blood samples were also collected for plasma suafrican torr quantification and PK analysis at various time points pre-dose and up to 72 hours post-dose. Thaumatin breast milk and plasma concentrations were measured using validated bioanalytical methods. Safety was assessed throughout the study by 12-lead ECG, vital sign measurement, columbia suicide severity rating scale (Columbia-Suicide SEVERITY RATING SCALE, C-SSRS) and incidence of Adverse Events (AEs).

The study drug was a yellow film coated tablet containing the excipients hydroxypropyl cellulose and magnesium stearate and a polymeric film coating

The total duration of the entire study (safety follow-up screening of the first subject to the last subject) was approximately 11 months.

The subject measures vital signs (blood pressure, pulse rate, temperature and respiratory rate) in a sitting or supine position and rests for at least 5 minutes before taking the measurement. The dominant arm was used for blood pressure and pulse rate measurements. Vital signs were collected on day 1, before and about 2 hours (blood pressure and pulse) and 4 hours (blood pressure and pulse) after the dose.

The subject performed a 12-lead ECG in a supine position and had a rest for at least 10 minutes before taking the measurement. On day 1, ECG was collected before and approximately 2 hours after dose.

The subject must be fasted for at least 8 hours prior to chemical and hematological blood withdrawal. All clinical laboratory tests were performed only at screening (allowing rescreening).

Screen/baseline C-SSRS version at screening, and versions since last visit on days-1 and 2 (or at ET).

Breast milk collection occurred on days 1-4-2 to 0 hours (pre-dose), 0-2, 2-4, 4-8, 8-12, 12-18, 24-32, 32-40, 40-48 and 48-72 hours post-dose.

Blood samples were collected for plasma PK assessment at time points 1, 1.5, 3, 6, 8.5, 10, 13, 15, 21, 24, 28, 36, 44 and 72 hours after dosing on day 1 prior to dosing. The general study procedure is summarized in table 6.

Table 6.

Standardized meals include those required on day-1, light breakfast at about 2.5 hours prior to dosing on day 1 (completed about 2 hours prior to dosing), then lunch at about 4 hours after dosing, dinner at about 8 hours after dosing, and snacks at about 11 hours after dosing and thereafter standardized meals.

Security follow-up telephone calls in from 30 days before screening to 5 to 7 days after checking off from the study facility (on day 4 or ET) were recorded.

Adverse events were monitored throughout the study by safety assessment, observation and subject reporting, including safety FU phone calls in 5-7 days (i.e., days 9-11) after sign-off from the study facility on day 4 or ET.

Breast milk collection the concentration of cord An Feituo in breast milk and plasma was evaluated based on pre-and post-dose samples collected on days 1 to 4. Breast milk was collected from both breasts using an electronic breast pump during time intervals from-2 to 0 hours prior to dose 1 day, and 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 18, 18 to 24, 24 to 32, 32 to 40, 40 to 48, and 48 to 72 hours after dose. The midpoint of each milk collection time interval is used as a time variable.

Breast milk is collected frequently as needed during specified time intervals, but at the end of each time interval, breast milk is pumped from both breasts and collected. At the end of each collection interval, all milk expressed from both breasts during that interval is pooled. The milk was thoroughly mixed by gently inverting the collection container 10 times to ensure uniformity of milk composition. The weight and volume of milk collected during each time interval was also recorded.

Serial blood samples (4 mL) were collected and dispensed into labeled K2EDTA tubes. The actual blood collection times for all samples were recorded on eCRF. The concentration of cable An Feituo in breast milk and plasma was determined at Origin bioanalytical laboratory using a validated bioanalytical method (LC-MS/MS). The analytical range of plasma suofatuo (lower limit of quantitation [ LLOQ ] to upper limit of quantitation) is 8.42 to 4210.00ng/mL, and the analytical range of breast milk suofatuo (lower limit of quantitation [ LLOQ ] to upper limit of quantitation) is 10.0 to 8000ng/mL.

By usingVersion 8.3 (Certara, inc., princetton, new Jersey, usa) and/orPharmacokinetic parameters were obtained from version 9.4 (SAS Institute, inc., cary, north Carolina, usa).

Subject criteria Each subject met the following criteria, healthy adult females aged 18 to 50 years (inclusive) upon consent, were enrolled in the group study; at least 50kg body weight and Body Mass Index (BMI) between 18 and 35kg/m ² inclusive, after delivery of a normal healthy infant between 10 days and 52 weeks inclusive before dosing time and active lactation from both breasts, if breast feeding is underway, stopping breast feeding its (or infants) between about 2 hours before dosing and about 72 hours after dosing, and resuming breast feeding after completion of the study day 4 program, or deciding to wean its infants before entering the study, agreeing to have had no nicotine-containing product including tobacco (cigarettes, cigars, chewing tobacco, snuff), e-cigarettes and nicotine lozenges/chewing gum/patches used for 3 days before dosing, using a medically acceptable contraceptive method at least 2 months before dosing on day 1, and using a medically acceptable contraceptive method during the entire study period and 30 days after completion of the study, when study is completed, and the study is designated, can be assured by the infants, and the multiple nutritional support factors can be met by ensuring that they take part in the study by the nutritional support of a multiple-taking-part milk bottle(s) and the nutritional support of their nutritional support (can be taken care) by the multiple study's) before taking part in the study's (continuous nutritional support of the need of their study, which is either completely vaccinated at least 14 days after the last dose (or the only dose) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [ covd-19 ]) vaccine, or alternatively not vaccinated prior to the study, wherein participants not completely vaccinated prior to the start of the study were selected to not receive any dose of COVID-19 vaccine and the study was continued.

Clinical laboratory tests including hematology, serum chemistry, urinalysis, and thyroexamination were collected only at the time of screening (thyroid panel).

A complete physical examination includes an assessment of at least the cardiovascular system, respiratory system, gastrointestinal system and nervous system. Height and weight were also measured and recorded. At screening and baseline/randomized visit, BMI was calculated from the field in order to verify eligibility.

Vital signs include oral temperature, pulse rate, respiratory rate, and BP. Clinically significant abnormal vital sign results reported during screening/randomization were recorded as medical history, and those reported after study drug were recorded as AE.

The subject evaluates blood pressure and pulse measurements in a sitting or supine position and rests for at least 5 minutes before taking the measurements. The dominant arm was used for blood pressure and pulse rate measurements. Vital signs were collected on day 1, before and about 2 hours (blood pressure and pulse) and 4 hours (blood pressure and pulse) after the dose.

12-Lead ECG was collected at screening, day-1 through day 4. A single 12-lead ECG is obtained using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT and corrects QT interval (QTc) intervals. Any abnormal safety assessment, including ECG readings, that is considered clinically significant in the medical and scientific judgment of the researcher is reported as AE. The researcher must review the ECG and record it in the source file. Clinically significant abnormal ECG results reported during screening were recorded as medical history, and those reported after study drug were recorded as AE.

All laboratory tests were performed according to the laboratory manual. The tests detailed in table 7 were performed by a central laboratory. Additional tests may be performed at any time during the study, as determined by the researcher to be necessary or as required by local regulations.

All laboratory tests with outliers that were considered clinically significant (and considered by the investigator to be relevant to the study drug) were repeated during the study or within 14 days after the last dose of study drug until the values returned to normal or baseline or the investigator or medical inspector no longer considered clinically significant. If the clinically significant values do not return to normal/baseline within a reasonable period of time as judged by the investigator, the etiology should be determined.

TABLE 7 safety laboratory test

● Urine drug screening (serum of phenylpropanamine and Bab during screening)

Bituins, benzodiazepinesClass, cocaine, urine at baseline (day-1)

Cannabis (marijuana), opiates, benzene

Cyclohexaniperidine

● Breath alcohol test

Alb=albumin, ALK-p=alkaline phosphatase, alt=alanine aminotransferase, ast=aspartate aminotransferase, bun=hematin nitrogen, ca=calcium, cbc=total blood count, CO 2-carbon dioxide, cl=chlorine, k=potassium, na=sodium, wbc=white blood count.

^* All subjects in the study were in need of pregnancy screening.

Statistics/analysis

Unless otherwise indicated, descriptive statistics were used to aggregate continuous data, including the number of subjects exposed (N) and the data to be aggregated (N), mean, standard Deviation (SD), median, minimum (min), maximum (max), geometric mean (geometric mean), coefficient of variation (CV%) and geometric coefficient of variation (CV%). The classification variables are presented using counts and percentages. UsingVersion 9.4 (SAS Institute, inc., cary, north Carolina, usa) generates analysis and summary outputs.

The PK population consisted of all subjects receiving study drug and provided breast milk or plasma PK data after at least one dose at the time interval or time point of collection. This population was used for evaluable PK concentration data and PK parameter summary and list. The safety population consisted of all subjects receiving the study drug dose. The population is used for demographic and baseline characteristics and for security data aggregation and listing.

Descriptive statistics were used to summarize pharmacokinetic concentrations and parameters including n, arithmetic mean, SD, coefficient of variation (CV%), median, min, max, geometric mean (geometric mean), and geometric coefficient of variation (Geo-CV%). For PK parameter t _max, only n, median, minimum and maximum values are presented.

A case-by-case evaluation is performed on subjects with partial data to determine if there is sufficient data available to reliably calculate PK parameters. In case of incomplete milk collection (partial/spilled samples, inaccurate total milk volume information for time-spaced samples), the time-spaced recovery is listed, but not included in the summary, and the cumulative recovery is reported only by the last previous complete milk collection. Data for time intervals during which the subject was unable to lactation (produce any milk) were treated as zero amounts (for the affected time intervals) in the cumulative recovery calculation sum.

Plasma and milk concentrations were pooled using descriptive statistics. For descriptive statistics calculations, concentrations below the lower limit of quantitation (BLQ) are treated as follows:

Summary statistics, each with one or more BLQ values, are calculated by assigning 1/2LLOQ to all values less than LLOQ. If the calculated arithmetic (and geometric) average is BLQ, then SD and CV% are presented as "ND" and the average is presented as "BLQ". However, since a high proportion of the BLQ value may affect SD, if a value exceeding 50% is input, the average value is not calculated for this point of time, and only the value of BLQ is presented again for the average value. Any minimum or median value calculated as BLQ within the summary statistics is presented as BLQ within the summary presentation.

The concentrations collected outside the sampling window allowed by the protocol were included in the descriptive statistics unless the PK scientist observed that the bias was substantial enough to affect the descriptive statistics. In this case, the excluded concentration is determined in the CSR.

With respect to plotting an arithmetic mean concentration profile, an arithmetic mean having one or more BLQ values at a time is calculated by assigning ¹/₂ LLOQ to all BLQ values. If the calculated average is BLQ, the time point is plotted as zero in the average pharmacokinetic curve. But since a high proportion of BLQ value may affect SD, if a value exceeding 50% is input, the average value is not calculated for this point in time, and the value of zero is plotted again. Lines with LLOQ tags are superimposed in the concentration axis to show LLOQ levels.

The security analysis is based on a security population. Secondary endpoints for evaluating subject safety and tolerability are AE incidence and laboratory test results reported by all subjects.

Adverse events recorded in the electronic case report table (eCRF) were encoded into SOC and PT using the medicated active medical dictionary (MedDRA). Adverse Events (TEAEs) occurring in treatment are defined as any event whose date of onset is on or after the date of the first dose of study medication, or any ongoing event of worsening severity after the date of the first dose of study medication, or any event that exists at baseline but is later considered by the researcher to be related to the medication until the end of the study. The incidence of TEAE is presented in terms of severity, association with study drug, start and end dates, severity and outcome. Researchers evaluate the severity of each AE and the correlation with study drugs. Columbia suicide severity rating scale (C-SSRS) data is summarized and listed in the scheduled visit. Other security analyses are performed as appropriate.

12 Lead ECG summarizing the number and percentage of subjects with clinically significant ECG interval abnormalities after a baseline of > 100 beats/min or < 60 beats/min ventricular rate, PR interval of > 200 milliseconds or < 120 milliseconds, QRS time period of > 100 milliseconds or < 80 milliseconds, QT interval of > 440 milliseconds or < 350 milliseconds, QTc Bazett and QTC FREDERICIA of > 470 milliseconds or < 330 milliseconds, RR interval of > 1200 milliseconds or < 600 milliseconds, and QTc Bazette and QTC FREDERICIA increases >30 milliseconds from the study baseline value.

Vital signs are exhibiting clinically significant vital sign abnormalities with an average systolic pressure of 150mmHg or less than 80mmHg, an average diastolic pressure of 95mmHg or less than 60mmHg, an average heart rate of 120bpm or less than 50bpm, a respiratory rate of <10 breaths/min or >24 breaths/min, a body temperature of >37.9 ℃ or <35.5 ℃, a systolic and diastolic pressure change of >20% relative to study baseline values/recordings, a pulse change of >20% relative to study baseline values/recordings, a body weight change of > 7% from the baseline values of the subject (weight loss/weight gain), and a body temperature change of >1.8% from the baseline temperature recordings of the subject.

Physical examination the physical examination data of each subject is presented in a list. Clinically significant adverse changes (i.e., exacerbations) found in physical examination after screening were recorded as AE.

A total of 6 subjects were grouped and treated in the study. All 6 subjects completed the study. No premature interruption was reported in the study. All 6 subjects received study drug (safety population) and provided post-dose breast milk or plasma PK data (PK population) for at least one collection time interval or time point. All 6 subjects were females and did not belong to spanish or latin families. The average (SD) of age, weight, height and BMI of the total population was 28.7 (5.54) years old, 79.15 (12.162) kg, 168.62 (6.013) cm and 27.90 (4.513) kg/m ², respectively.

TABLE 8 demographic and baseline characteristics (Security population)

BMI = body mass index; N = number of subjects exposed

Note that the percentages are based on N.

Prior and concomitant medication two subjects took the medication for AE during the study. One subject received acetaminophen and the other subject received ibuprofen.

Medical history and surgical history a total of 5 out of 6 subjects had medical and surgical histories. Of these subjects, 1 had a history of appendectomy, caesarean section and tubal ligation. One subject had asthma and caesarean section. One subject had cholelithiasis, pancreatitis, and cholecystectomy. One subject had umbilical hernia repair, heartburn, and caesarean section, and 1 subject had natural labor and hip pain caused by natural labor.

Reference is made to:

Czosnykowska- M., krdylak-Olejnik, B., and Orczyk M.(2018).Breast Milk Macronutrient Components in Prolonged Lactation.Nutrients,10(12),1893.Doi:10.3390/nu10121893.

Jones B.E. (2000) Basic mechanisms of sleep-wake states, see Kryger, M.H., roth, T., and demand, W.C., code PRINCIPLES AND PRACTICE of SLEEP MEDICINE, 3 rd edition Philadelphia: W.B Saunders, pages 134-154.

Li Y., panossian, L.A., zhang, J., zhu, Y., zhan, G, chou, Y.T., fenik, P., bhatnagar, S., piel, D.A., beck, S.G., and Veasey,S.(2014).Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response.Sleep,37(1),51-64.Doi:10.5665/sleep.3306.

Lockwood P.A.,Pauer,L.,Scavone,J.M.,Allard,M.,Mendes da Costa,L.,Alebic-Kolbah,T.,Plotka,A.,Alvey,C.W., And Chew,M.L.(2016).The Pharmacokinetics of Pregabalin in Breast Milk,Plasma,and Urine of Healthy Postpartum Women.Journal of human lactation:official journal of International Lactation Consultant Association,32(3),NP1-NP8.Doi:10.1177/0890334415626148.

Posner K.,Brown,G.K.,Stanley,B.,Brent,D.A.,Yershova,K.V.,Oquendo,M.A.,Currier,G.W.,Melvin,G.A.,Greenhill,L.,Shen,S., And Mann,J.J.(2011).The Columbia-Suicide Severity Rating Scale:initial validity and internal consistency findings from three multisite studies with adolescents and adults.The American journal of psychiatry,168(12),1266-1277.Doi:10.1176/appi.ajp.2011.10111704.

Siegel J.M. brain MECHANISMS GENERATING REM sleep, see PRINCIPALS AND PRACTICE of SLEEP MEDICINE, second edition M.K.Kryger, T.Roth, W.C.Dement, new York: saunders,2000.

Tsujino n., tsunematsu, t., uchigashima, m., konno, k., yamanaka, a., kobayashi, k., watanabe, m., koyama, y., and Sakurai,T.(2013).Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice.PloS one,8(7),e70012.Doi:10.1371/journal.pone.0070012.

US Food and Drug Administration.Center for Drug Evaluation and Research(2019).Guidance for Industry.Clinical Lactation Studies:Considerations for Study Design.Draft guidance.Center for Drug Evaluation and Research,US Food and Drug Administration,Rockville,MD.

US Food and Drug Administration.Center for Drug Evaluation and Research.May 2019.Guidance for Industry.Clinical Lactation Studies:Considerations for Study Design.Draft guidance.Center for Drug Evaluation and Research,US Food and Drug Administration,Rockville,MD.

Wisor j.p., nishino, s., sora, i., uhl, g.h., mignot, e., and Edgar,D.M.(2001).Dopaminergic role in stimulant-induced wakefulness.The Journal of neuroscience:the official journal of the Society for Neuroscience,21(5),1787-1794.Doi:10.1523/JNEUROSCI.21-05-01787.2001.

Wu x., jackson, r.t., khan, s.a., ahuja, j., and Pehrsson,P.R.(2018).Human Milk Nutrient Composition in the United States:Current Knowledge,Challenges,and Research Needs.Current developments in nutrition,2(7),nzy025.Doi:10.1093/cdn/nzy025.

Zhu y, fenik, p., zhan, g., xin, r., and Veasey,S.C.(2015).Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea.Frontiers in neurology,6,109.Doi:10.3389/fneur.2015.00109.

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein. All publications, patent applications, patents, patent publications, and any other references cited herein are incorporated by reference in their entirety to provide teachings relating to the sentences and/or paragraphs in which the references appear.

Claims

1. A method of reducing exposure to Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising:

orally administering Soanfito to the subject at a daily dose of about 37.5 mg to about 300 mg; and

The infant is fed breast milk from the subject at least about 5 hours after administration of Soanfitol to the subject, thereby reducing the infant's exposure to Soanfitol.

2. The method of claim 1, wherein the method provides an infant daily dose of Soanfito of about 0.3 mg or less.

3. The method of claim 1, wherein the method achieves a relative infant dose that is less than about 9% of the subject's weight-adjusted dose.

4. The method of claim 3, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

5. The method of claim 1, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

6. The method of claim 1, wherein the subject is 1 day to 24 months postpartum.

7. The method of claim 6, wherein the subject is 10 days to 12 months postpartum.

8. The method of claim 1, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit/hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

9. The method of claim 1, wherein the subject is a female between the ages of 18 and 45.

10. The method of claim 1, wherein the daily dose of Soanfito is 150 mg.

11. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising:

orally administering Soanfito to the subject at a daily dose of between 37.5 mg and 300 mg; and

The infant is fed breast milk from the subject for at least about 5 hours after administration of Soanfitol to the subject, thereby reducing the likelihood of an adverse event in the infant caused by Soanfitol.

12. The method of claim 11, wherein the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

13. The method of claim 11, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit/hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

14. The method of claim 11, wherein the method provides an infant daily dose of Soanfitol of about 0.3 mg or less.

15. The method of claim 11, wherein the relative infant dose is less than about 9% of the subject's weight-adjusted dose.

16. The method of claim 15, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

17. The method of claim 11, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

18. The method of claim 11, wherein the subject is 1 day to 24 months postpartum.

19. The method of claim 18, wherein the subject is 10 days to 12 months postpartum.

20. The method of claim 11, wherein the daily dose of Soanfito is 150 mg.

21. The method of claim 11, wherein the subject is a female between the ages of 18 and 45.

22. A method for treating a disorder treatable with Soanfito in a subject producing breast milk for feeding an infant, comprising:

Reducing the infant's exposure to Soanfitol and/or reducing the likelihood of an adverse event in the infant who is fed from the subject's breast milk comprises feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfitol to the subject.

23. The method of claim 22, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit/hyperactivity disorder, depression, or binge eating disorder.

24. The method of claim 22, wherein the method provides an infant daily dose of Soanfitol of about 0.3 mg or less.

25. The method of claim 22, wherein the method achieves a relative infant dose that is less than about 9% of the subject's weight-adjusted dose.

26. The method of claim 25, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

27. The method of claim 22, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

28. The method of claim 22, wherein the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

29. The method of claim 22, wherein the subject is 1 day to 24 months postpartum.

30. The method of claim 29, wherein the subject is 10 days to 12 months postpartum.

31. The method of claim 22, wherein the subject is a female between the ages of 18 and 45.

32. The method of claim 22, wherein the daily dose of Soanfito is 150 mg.

33. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising:

orally administering Soanfito to the mother at a once daily dose of about 150 mg; and

feeding the infant breast milk obtained from the mother at least about 5 hours after administering Soanfito to the mother;

wherein the infant daily dose of Soanfito is reduced to about 0.3 mg or less; and

wherein the likelihood of adverse events in the infant being caused by Soanfito is reduced.

34. The method of claim 33, wherein the adverse event is agitation, insomnia, anorexia, or decreased weight gain.

35. The method of claim 33, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

36. The method of claim 33, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

37. The method of claim 33, wherein the lactating mother is 1 day to 24 months postpartum.

38. The method of claim 33, wherein the lactating mother is 10 days to 12 months postpartum.

39. The method of claim 33, wherein the lactating mother is between 18 and 45 years old.

40. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising:

orally administering Soanfito to the mother at a once daily dose of about 75 mg; and

wherein the infant daily dose of Soanfito is reduced to about 0.15 mg or less; and

41. The method of claim 40, wherein the adverse event is agitation, insomnia, anorexia, or decreased weight gain.

42. The method of claim 40, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

43. The method of claim 40, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

44. The method of claim 40, wherein the lactating mother is 1 day to 24 months postpartum.

45. The method of claim 40, wherein the lactating mother is 10 days to 12 months postpartum.

46. The method of claim 40, wherein the lactating mother is between 18 and 45 years old.

47. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising:

wherein said infant's exposure to soanfito from said breast milk is reduced.

48. The method of claim 47, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

49. The method of claim 47, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

50. The method of claim 47, wherein the lactating mother is 1 day to 24 months postpartum.

51. The method of claim 47, wherein the lactating mother is 10 days to 12 months postpartum.

52. The method of claim 47, wherein the lactating mother is between 18 and 45 years old.

53. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising:

wherein said infant's exposure to soanfito from said breast milk is reduced.

54. The method of claim 53, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

55. The method of claim 53, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

56. The method of claim 53, wherein the lactating mother is 1 day to 24 months postpartum.

57. The method of claim 53, wherein the lactating mother is 10 days to 12 months postpartum.

58. The method of claim 53, wherein the nursing mother is between 18 and 45 years old.

59. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising:

orally administering Soanfito to the subject at a once daily dose of about 150 mg; and

feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject;

60. The method of claim 59, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

61. The method of claim 59, wherein the subject is 1 day to 24 months postpartum.

62. The method of claim 59, wherein the subject is 10 days to 12 months postpartum.

63. The method of claim 59, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

64. The method of claim 63, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

65. The method of claim 63, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

66. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising:

orally administering Soanfito to the subject at a once daily dose of about 75 mg; and

67. The method of claim 66, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

68. The method of claim 66, wherein the subject is 1 day to 24 months postpartum.

69. The method of claim 66, wherein the subject is 10 days to 12 months postpartum.

70. The method of claim 66, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

71. The method of claim 70, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

72. The method of claim 70, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

73. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising:

wherein said infant's exposure to soanfito from said breast milk is reduced.

74. The method of claim 73, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

75. The method of claim 73, wherein the subject is 1 day to 24 months postpartum.

76. The method of claim 73, wherein the subject is 10 days to 12 months postpartum.

77. The method of claim 73, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

78. The method of claim 77, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

79. The method of claim 77, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

80. (New) A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising:

wherein said infant's exposure to soanfito from said breast milk is reduced.

81. The method of claim 80, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

82. The method of claim 80, wherein the subject is 1 day to 24 months postpartum.

83. The method of claim 80, wherein the subject is 10 days to 12 months postpartum.

84. The method of claim 80, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

85. The method of claim 84, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

86. The method of claim 84, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

87. A method of reducing the risk of agitation in an infant fed breast milk obtained from a subject treated with Soanfito, comprising:

orally administering Soanfito to the subject at a daily dose of about 150 mg; and

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

88. The method of claim 87, wherein the infant does not experience agitation resulting from Soanfitol exposure.

89. The method of claim 87, wherein the subject is 1 day to 24 months postpartum.

90. The method of claim 87, wherein the subject is 11 days to 12 months postpartum.

91. The method of claim 87, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

92. The method of claim 91, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

93. The method of claim 91, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

94. The method of claim 87, wherein the subject is being treated with Soanfito to improve wakefulness.

95. The method of claim 87, wherein the subject is a female between the ages of 18 and 50.

96. A method of reducing the risk of agitation in a breastfed infant obtained from a subject treated with Soanfito, comprising:

orally administering Soanfito to the subject at a daily dose of about 75 mg; and

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

97. The method of claim 96, wherein the infant does not experience agitation resulting from Soanfitol exposure.

98. The method of claim 96, wherein the subject is 1 day to 24 months postpartum.

99. The method of claim 96, wherein the subject is 11 days to 12 months postpartum.

100. The method of claim 96, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

101. The method of claim 100, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

102. The method of claim 100, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

103. The method of claim 96, wherein the subject is being treated with Soanfito to improve wakefulness.

104. The method of claim 96, wherein the subject is a female between the ages of 18 and 50.

105. A method of reducing the risk of insomnia in a breastfed infant obtained from a subject treated with Soanfito, comprising:

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

106. The method of claim 105, wherein the infant does not experience insomnia caused by Soanfito exposure.

107. The method of claim 105, wherein the subject is 1 day to 24 months postpartum.

108. The method of claim 105, wherein the subject is 11 days to 12 months postpartum.

109. The method of claim 105, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

110. The method of claim 109, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

111. The method of claim 109, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

112. The method of claim 105, wherein the subject is being treated with Soanfito to improve wakefulness.

113. The method of claim 105, wherein the subject is a female between the ages of 18 and 50.

114. A method of reducing the risk of insomnia in an infant fed breast milk obtained from a subject treated with Soanfito, comprising:

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

115. The method of claim 114, wherein the infant does not experience insomnia caused by Soanfito exposure.

116. The method of claim 114, wherein the subject is 1 day to 24 months postpartum.

117. The method of claim 114, wherein the subject is 11 days to 12 months postpartum.

118. The method of claim 114, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

119. The method of claim 118, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

120. The method of claim 118, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

121. The method of claim 114, wherein the subject is being treated with Soanfito to improve wakefulness.

122. The method of claim 114, wherein the subject is a female between the ages of 18 and 50.

123. A method of reducing the risk of anorexia and/or decreased weight gain in a breastfed infant obtained from a subject treated with Soanfito, comprising:

feeding the infant with breast milk obtained from the subject at least about 5 hours after administration of Soanfitol to the subject,

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

124. The method of claim 123, wherein the infant does not experience anorexia, decreased weight gain, or weight loss resulting from Soanfito exposure.

125. The method of claim 123, wherein the subject is 1 day to 24 months postpartum.

126. The method of claim 123, wherein the subject is 11 days to 12 months postpartum.

127. The method of claim 123, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

128. The method of claim 127, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

129. The method of claim 127, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

130. The method of claim 123, wherein the subject is being treated with Soanfito to improve wakefulness.

131. The method of claim 123, wherein the subject is a female between the ages of 18 and 50.

132. A method of reducing the risk of anorexia and/or decreased weight gain in a breastfed infant obtained from a subject treated with Soanfito, comprising:

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

133. The method of claim 132, wherein the infant does not experience anorexia, decreased weight gain, or weight loss resulting from Soanfito exposure.

134. The method of claim 132, wherein the subject is 1 day to 24 months postpartum.

135. The method of claim 132, wherein the subject is 11 days to 12 months postpartum.

136. The method of claim 132, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

137. The method of claim 136, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

138. The method of claim 136, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

139. The method of claim 132, wherein the subject is being treated with Soanfito to improve wakefulness.

140. The method of claim 132, wherein the subject is a female between the ages of 18 and 50.

141. A method of preventing a decrease in the number of feedings and/or a decrease in the volume of milk consumed by a breastfed infant obtained from a subject treated with Soanfito, comprising:

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

142. The method of claim 141, wherein the infant does not experience a decrease in the number of feedings and/or a decrease in the volume of milk consumed as a result of Soanfito exposure.

143. The method of claim 141, wherein the subject is 1 day to 24 months postpartum.

144. The method of claim 141, wherein the subject is 11 days to 12 months postpartum.

145. The method of claim 141, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

146. The method of claim 145, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

147. The method of claim 145, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

148. The method of claim 141, wherein the subject is being treated with Soanfito to improve wakefulness.

149. The method of claim 141, wherein the subject is a female between the ages of 18 and 50.

150. A method of preventing a decrease in the number of feedings and/or a decrease in the volume of milk consumed by a breastfed infant obtained from a subject treated with Soanfito, comprising:

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

151. The method of claim 150, wherein the infant does not experience a decrease in the number of feedings and/or a decrease in the volume of milk consumed as a result of Soanfito exposure.

152. The method of claim 150, wherein the subject is 1 day to 24 months postpartum.

153. The method of claim 150, wherein the subject is 11 days to 12 months postpartum.

154. The method of claim 150, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

155. The method of claim 154, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

156. The method of claim 154, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

157. The method of claim 150, wherein the subject is being treated with Soanfito to improve wakefulness.

158. The method of claim 150, wherein the subject is a female between the ages of 18 and 50.

159. A method of preventing an infant of a nursing human mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, the method comprising withholding from the infant breast milk obtained within at least about 3.5 hours of the mother receiving a once daily oral dose of about 150 mg of Soanfitol, wherein the median _Tmax of Soanfitol excreted in the breast milk is about 1.1 hours,

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

160. The method of claim 159, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

161. The method of claim 159, wherein the infant does not experience agitation due to exposure to Soanfitol.

162. The method of claim 159, wherein the infant does not experience sleeplessness due to exposure to Soanfito.

163. The method of claim 159, wherein the infant does not experience anorexia and/or decreased weight gain due to exposure to Soanfito.

164. The method of claim 159, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:1.

165. The method of claim 159, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

166. The method of claim 159, wherein breast milk produced by the nursing mother during the at least about 3.5 hours that the mother receives the once daily oral dose of Soanfito is expressed and discarded.

167. The method of claim 159, wherein the mother is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

168. The method of claim 167, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

169. The method of claim 167, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

170. The method of claim 159, wherein the mother is being treated with Soanfito to improve wakefulness.

171. The method of claim 159, wherein the nursing mother is from about 1 day to about 24 months postpartum.

172. The method of claim 159, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

173. The method of claim 159, wherein the lactating mother is between 18 and 45 years old.

174. A method of preventing an infant of a nursing human mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, the method comprising withholding from the infant breast milk obtained within at least about 3.5 hours of the mother receiving a once daily oral dose of about 75 mg of Soanfitol, wherein the median _Tmax of Soanfitol excreted in the breast milk is about 1.1 hours,

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

175. The method of claim 174, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

176. The method of claim 174, wherein the infant does not experience agitation due to exposure to Soanfitol.

177. The method of claim 174, wherein the infant does not experience insomnia due to exposure to Soanfito.

178. The method of claim 174, wherein the infant does not experience anorexia and/or decreased weight gain due to exposure to Soanfito.

179. The method of claim 174, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:1.

180. The method of claim 174, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

181. The method of claim 174, wherein breast milk produced by the nursing mother during the at least about 3.5 hours that the mother receives the once daily oral dose of Soanfito is expressed and discarded.

182. The method of claim 174, wherein the mother is being treated with Soanfitol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

183. The method of claim 182, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

184. The method of claim 182, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

185. The method of claim 174, wherein the mother is being treated with Soanfito to improve wakefulness.

186. The method of claim 174, wherein the nursing mother is from about 1 day to about 24 months postpartum.

187. The method of claim 174, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

188. The method of claim 174, wherein the lactating mother is between 18 and 45 years old.

189. A method of reducing exposure to soanfitol from breast milk of an infant receiving breast milk from a nursing human mother who is being treated with a once daily dose of about 150 mg of soanfitol for a disorder amenable to treatment with soanfitol, the method comprising feeding the infant breast milk obtained from the mother at least about 5 hours after administration of soanfitol to the mother, wherein the infant's exposure to soanfitol is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of soanfitol, and

The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

190. The method of claim 189, wherein the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose.

191. The method of claim 189, wherein the breast milk is obtained from the mother at least about 7 hours after administration of Soanfitol to the mother.

192. The method of claim 189, wherein the breast milk is obtained from the mother at least about 10 hours after administration of Soanfitol to the mother.

193. The method of claim 189, wherein breast milk produced by the nursing mother during the at least about 5 hours after administration of Soanfitol to the mother is expressed and discarded.

194. The method of claim 189, wherein the infant does not experience agitation due to exposure to Soanfitol.

195. The method of claim 189, wherein the infant does not experience insomnia due to exposure to Soanfito.

196. The method of claim 189, wherein the infant does not experience anorexia and/or decreased weight gain due to exposure to Soanfito.

197. The method of claim 189, wherein the mother is being treated with Soanfitol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

198. The method of claim 197, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

199. The method of claim 197, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

200. The method of claim 189, wherein the mother is being treated with Soanfito to improve wakefulness.

201. The method of claim 189, wherein the nursing mother is from about 1 day to about 24 months postpartum.

202. The method of claim 189, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

203. The method of claim 189, wherein the lactating mother is between 18 and 45 years old.

204. A method of reducing exposure to soanfitol from breast milk of an infant receiving breast milk from a nursing human mother who is being treated with a once daily dose of about 75 mg of soanfitol for a disorder amenable to treatment with soanfitol, the method comprising feeding the infant breast milk obtained from the mother at least about 5 hours after administration of soanfitol to the mother, wherein the infant's exposure to soanfitol is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of soanfitol, and

The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

205. The method of claim 204, wherein the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose.

206. The method of claim 204, wherein the breast milk is obtained from the mother at least about 7 hours after administration of Soanfito to the mother.

207. The method of claim 204, wherein the breast milk is obtained from the mother at least about 10 hours after administration of Soanfitol to the mother.

208. The method of claim 204, wherein breast milk produced by the nursing mother during the at least about 5 hours after administration of Soanfitol to the mother is expressed and discarded.

209. The method of claim 204, wherein the infant does not experience agitation due to exposure to Soanfitol.

210. The method of claim 204, wherein the infant does not experience insomnia due to exposure to Soanfito.

211. The method of claim 204, wherein the infant does not experience anorexia and/or decreased weight gain due to exposure to Soanfitol.

212. The method of claim 204, wherein the mother is being treated with Soanfitol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

213. The method of claim 212, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

214. The method of claim 212, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

215. The method of claim 204, wherein the mother is being treated with Soanfito to improve wakefulness.

216. The method of claim 204, wherein the lactating mother is from about 1 day to about 24 months postpartum.

217. The method of claim 204, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

218. The method of claim 204, wherein the lactating mother is between 18 and 45 years old.

219. A method of treating excessive daytime sleepiness in a lactating human mother whose infant is at risk for an adverse event caused by the mother's excessive daytime sleepiness, and wherein the lactating human mother desires to breastfeed the infant, the method comprising:

a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant,

(b) providing the mother who has an ESS total score of 15 or greater and experiences sleep attacks while caring for the infant with a starting dose of Soanfitol: 37.5 mg once daily if the excessive daytime sleepiness is associated with obstructive sleep apnea, or 75 mg once daily if the excessive daytime sleepiness is associated with narcolepsy, and doubling the dose at intervals of at least 3 days up to 150 mg once daily; and

(c) feeding the infant breast milk obtained from the mother at least about 3.5 hours after administration of Soanfitol to the mother, thereby avoiding exposure of the infant to the maximum concentration of Soanfitol in the breast milk,

wherein the median _Tmax of Soanfidol excreted in breast milk is approximately 1.1 hours, and

The infant daily dose of Soanfito was reduced to about 0.3 mg or less after the 150 mg dose, to about 0.15 mg or less after the 75 mg dose, and to about 0.08 mg or less after the 37.5 mg dose.

220. The method of claim 219, wherein the lactating mother experiences a decrease in ESS total score of 5 or more.

221. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while holding the infant.

222. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while feeding the infant.

223. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while nursing the infant.

224. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of automatic movements while caring for the infant.

225. The method of claim 219, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

226. The method of claim 219, wherein the infant does not experience agitation due to exposure to soanfitol in the breast milk.

227. The method of claim 219, wherein the infant does not experience sleeplessness due to exposure to Soanfitol in the breast milk.

228. The method of claim 219, wherein the infant does not experience anorexia and/or decreased weight gain due to exposure to soanfitol in the breast milk.

229. The method of claim 219, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:1.

230. The method of claim 219, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

231. The method of claim 219, wherein breast milk produced by the mother during the at least about 3.5 hours after administration of Soanfitol to the mother is expressed and discarded.

232. The method of claim 219, wherein the lactating mother is from about 1 day to about 24 months postpartum.

233. The method of claim 219, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

234. The method of claim 219, wherein the lactating mother is between 18 and 45 years old.

235. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a human subject treated with Soanfitol, comprising:

feeding the infant breast milk from the subject at least about 5 hours after administration of Soanfito to the subject,

The cumulative amount of Soanfidol excreted in breast milk within 8 hours is reduced to about 0.26 mg or less.

236. The method of claim 235, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

237. The method of claim 235, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit/hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

238. The method of claim 235, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

239. The method of claim 235, wherein the lactating mother is 1 day to 24 months postpartum.

240. The method of claim 239, wherein the subject is 10 days to 52 weeks postpartum.

241. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a human subject treated with Soanfitol, comprising:

The cumulative amount of Soanfidol excreted in breast milk within 24 hours is reduced to about 0.35 mg or less.

242. The method of claim 241, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

243. The method of claim 241, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit/hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

244. The method of claim 241, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

245. The method of claim 241, wherein the lactating mother is 1 day to 24 months postpartum.

246. The method of claim 245, wherein the subject is 10 days to 52 weeks postpartum.

247. A method for treating a disorder treatable with Soanfito in a human subject producing breast milk for feeding an infant, comprising:

reducing the infant's exposure to Soanfitol and/or reducing the likelihood of an adverse event in the infant who is fed from the subject's breast milk, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfitol to the subject,

The cumulative median amount of sulphatol excreted in breast milk within 8 hours was reduced to approximately 0.26 mg or less.

248. The method of claim 247, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit/hyperactivity disorder, depression, or binge eating disorder.

249. The method of claim 247, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

250. The method of claim 247, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

251. The method of claim 247, wherein the subject is 1 day to 24 months postpartum.

252. The method of claim 251, wherein the subject is 10 days to 52 weeks postpartum.

253. The method of claim 247, wherein the subject is a female between the ages of 18 and 45.

254. A method for treating a disorder treatable with Soanfito in a human subject producing breast milk for feeding an infant, comprising:

The cumulative median amount of Soanfidol excreted in breast milk within 24 hours was reduced to about 0.35 mg or less.

255. The method of claim 254, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit/hyperactivity disorder, depression, or binge eating disorder.

256. The method of claim 254, wherein the infant does not experience restlessness, insomnia, or decreased weight gain resulting from Soanfito exposure.

257. The method of claim 254, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

258. The method of claim 254, wherein the subject is 1 day to 24 months postpartum.

259. The method of claim 258, wherein the subject is 10 days to 52 weeks postpartum.

260. The method of claim 254, wherein the subject is a female between the ages of 18 and 45.