HK40007948A - Formulation for inhibiting formation of 5-ht 2b agonists and methods of using same - Google Patents

Description

For inhibiting 5-HT2BFormed formulations of agonists and methods of use thereof

Technical Field

The present invention relates generally to the field of medicinal chemistry, and more specifically to inhibiting effects on 5-HT_2BPharmaceutical compositions that form metabolites of the receptor and thereby reduce adverse side effects; and more particularly to a combination of fenfluramine (fenfluramine) and a pharmaceutical agent that inhibits the formation of desfenfluramine (norfenfluramine).

Background

Drug discovery to identify antiepileptic drugs that are effective against intractable epilepsy is a formidable challenge. The underlying causes are diverse and poorly understood. Many antiepileptic drugs ("AEDs") are ineffective, and even contraindicated, because they exacerbate symptoms. Their mechanism of action can often be complex and often not fully characterized. Therefore, it is difficult to predict the efficacy of new drugs, even those related to known potent drug structures. Another difficulty is that patients who participate in clinical trials are often treated with a variety of medications which, while not eliminating seizures, keep them relatively stable. Their ability to modify their treatment is extremely limited because their condition deteriorates and becomes severe, and often life-threatening symptoms reappear.

Nevertheless, a breakthrough was made. One important breakthrough is fenfluramine, which has proven to be very effective in treating refractory epilepsy including dravir (Dravet) syndrome, renoxx-Gastaut (Lennox-Gastaut) syndrome, dutch (dose) syndrome, and West (West) syndrome. Delaviru syndrome or severe myoclonic epilepsy in infancy is a rare malignant epileptic syndrome. This type of epilepsy has an early onset in previously healthy children and is refractory to most conventional antiepileptic drugs. Similarly, renoxer-stokes syndrome, dorzem syndrome, and wester syndrome are serious diseases that are equally refractory to conventional therapy. Prior to fenfluramine, there was little reliable and effective treatment for any of those conditions, nor was there a treatment capable of completely eliminating seizures for a long period of time.

Fenfluramine, also known as 3-trifluoromethyl-N-ethylphenylamine, is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. Although the mechanism by which it reduces seizures is not well understood, fenfluramine increases the level of 5-hydroxytryptamine (serotonin), a neurotransmitter that regulates mood, appetite, and other functions. It causes the release of 5-hydroxytryptamine by disrupting vesicular storage of neurotransmitters and reversing 5-hydroxytryptamine transporter function. It is also known to act directly on 5HT receptors, in particular 5HT1D, 5HT2A, 5HT2C and 5HT 7. It has no significant agonistic effect on the 5HT2B receptor.

Fenfluramine is cleared from plasma by renal excretion and metabolized by the liver to desfenfluramine by cytochrome P450 enzymes in the liver, predominantly CYP1a2, CYP2B6 and CYP2D6, but CYP2C9, CYP2C19 and CYP3a4 also contribute to fenfluramine clearance. See fig. 7A. This metabolism involves the production of a deethylated metabolite of defecanflamine, e.g., defecanflamine as shown below, by the cleavage of the N-ethyl group by the CYP450 enzyme.

Fenfluramine was originally marketed under the trade names pondiin, Ponderax and adimax as an appetite suppressant, but was withdrawn from the us market in 1997 after a report of valvulopathy including the condition known as myocardial fibrosis and pulmonary hypertension. It was subsequently withdrawn from other markets around the world. The unique valvular abnormality seen with fenfluramine is the thickening of the leaflets and chordae tendineae (chordae).

One mechanism for explaining this phenomenon involves the heart valve 5-hydroxytryptamine receptor, which is thought to help regulate growth. The 5-HT2B receptor is abundant in the human heart valves. Since desfenfluramine is a particularly potent 5-HT2B agonist, fenfluramine and its active metabolite desfenfluramine stimulate the 5-hydroxytryptamine receptor, which may lead to the discovery of valvular abnormalities in patients taking fenfluramine. In support of this notion, this valvular abnormality also occurs in patients using other drugs acting on the 5-HT2B receptor.

More generally, many highly potent drugs, such as fenfluramine, are associated with significant risks due to active metabolites with toxic effects. The nature and severity of these risks strongly influence the feasibility of the drug as a therapeutic agent and its marketability, and there are many examples of highly potent drugs that are withdrawn due to safety concerns.

Accordingly, there is a need in the art for methods of using fenfluramine for the treatment of fenfluramine-responsive diseases and conditions that reduce patient exposure to harmful metabolites while maintaining therapeutically effective levels of fenfluramine. There is also a need in the art for new therapies for pediatric epilepsy that are safe and effective and refractory.

Disclosure of Invention

Provided herein are compositions and methods for reducing exposure of a patient to harmful metabolites of a drug used to treat the patient. For example, the present disclosure provides methods and compositions for reducing exposure to drug metabolites with potentially harmful activity mediated by the 5-HT2B receptor.

In one aspect, the present disclosure provides a method of inhibiting the production of an adverse metabolite in a subject treated with a drug that is metabolized to one or more adverse metabolites, wherein the drug is co-administered with one or more metabolic inhibitors.

In one embodiment, the drug is fenfluramine or a pharmaceutically acceptable salt thereof and is co-administered with a metabolic inhibitor such as cannabidiol (cannabidiol).

In an alternative embodiment, the medicament, e.g. fenfluramine, is co-administered with one or more metabolic inhibitors selected from inhibitors of one or more metabolic enzymes selected from the group consisting of CYP1a2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3a 4.

In an alternative embodiment of this aspect, fenfluramine or a pharmaceutically acceptable salt thereof is co-administered with one or more agents selected from the group comprising stiripentol (stiipetol), oxazepam (clobazam) and cannabidiol.

In alternative exemplary embodiments, fenfluramine or a pharmaceutically acceptable salt thereof is co-administered with stiripentol, or with cannabidiol, or with oxapicloram.

In alternative exemplary embodiments, fenfluramine or a pharmaceutically acceptable salt thereof is co-administered with cannabidiol and sethoxydim, or cannabidiol and oxazepine, or sethoxydim and oxazepine.

In an exemplary embodiment, fenfluramine active agent is co-administered with all of stiripentol, cannabidiol and oxapicloram.

In another aspect, the present disclosure provides methods of treating epilepsy or a neurological-related disorder by co-administering to a subject fenfluramine or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more metabolic inhibitors.

In alternative embodiments, the neuro-related disorder is delaviru syndrome, or renox-gares syndrome, or dorzoles syndrome, or westst syndrome.

In yet another aspect, the present disclosure provides a method for suppressing appetite in a subject by co-administering to the subject fenfluramine or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more metabolic inhibitors.

Pharmaceutical compositions for practicing the subject methods are also provided.

One aspect of the invention is a formulation for inhibiting the metabolism of a first drug characterized by the formation of metabolites with adverse reactions, the formulation comprising:

the first drug and a second drug in the form of a CYP450 enzyme inhibitor,

wherein the CYP450 enzyme inhibitor down-regulates the formation of the metabolite of the first drug.

Another aspect of the invention is a formulation for treating a patient, the formulation comprising:

a first agent characterized by acting on a 5-HT receptor, and further characterized by the formation of a metabolite that acts on the 5-HT2B receptor with a known adverse effect; and

a second drug in the form of a CYP450 enzyme inhibitor,

wherein the CYP inhibitor down-regulates the formation of the metabolite of the first drug.

Yet another aspect of the invention is a formulation for preventing, reducing or ameliorating seizures in a patient diagnosed with a neurological disease, the formulation comprising:

a first agent characterized by the formation of a metabolite that acts on the 5-HT receptor, and acts on the 5-HT2B receptor with a known adverse effect; and

a second drug in the form of a CYP inhibitor,

wherein the CYP inhibitor down-regulates the formation of the metabolite of the first drug.

Yet another aspect of the invention is a formulation for use as described above, wherein the patient is diagnosed with a form of refractory epilepsy.

Yet another aspect of the invention is a formulation for use as described above, wherein the refractory epilepsy is in a form selected from the group consisting of delavir syndrome, renox-gares syndrome, dorze syndrome and westster syndrome.

One aspect of the invention is a formulation for suppressing appetite in a subject, the formulation comprising:

a first agent characterized by the formation of a metabolite that acts on the 5-HT receptor, and acts on the 5-HT2B receptor with a known adverse effect; and

a second drug in the form of a CYP inhibitor,

wherein the CYP inhibitor down-regulates the formation of the metabolite of the first drug.

A further aspect of the present invention is the formulation for use as described above, wherein the first drug is fenfluramine and the harmful metabolite is desfenfluramine.

Yet another aspect of the invention is a formulation for the above use, wherein the one or more metabolic inhibitors is a CYP450 inhibitor.

Yet another aspect of the present invention is the formulation for the above use, wherein the CYP450 inhibitor is selected from the group consisting of a CYP1a2 inhibitor, a CYP2B6 inhibitor, a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor and a CYP3a4 inhibitor.

A further aspect of the invention is a formulation for the above use, wherein the one or more metabolic inhibitors are selected from the group consisting of stiripentol, oxapicloram and cannabidiol.

A further aspect of the invention is a formulation for use as described above, wherein the CYP inhibitor is cannabidiol.

A further aspect of the invention is a formulation for the above use, further comprising co-administering to the subject an effective amount of a co-therapeutic agent selected from the group consisting of acetyl amine (acetazolamide), barbituron (barbixaclone), beclomemide (beclamide), bravacetam (bravaracetam), bupropion (buprperon), cinapralan (cinacalet), oxazepam, clonazepam (clonazepam), lorazepam (clorazepate), diazepam (diazepam), dipropionic acid (divalproproe), eslicarbazepine acetate (eslicarbazepineacetate), ethione (ethodione), ethiofetin (ethotoxin), felbamate (fenbazin), gabapentin (gabapentin), clavulanamide (osamide), milnacaloamide (milnacaloamide), methacylamine (methazamide (methazolamide), acetofenazamide (fenazamide), acetofenamide (fenamide (fenazamide (methamide), acetofenamide (fenamide (methamide (fenamide), acetofenamide (fenamide (methamide (fenamide), acetofenamide (e), acetofenamide (methamide (fenamide (e), acetofenamide (methamide (e), acetofenamide (methamide (e), acetofenamide (methamide (e), acetofena, Examples of pharmaceutically acceptable salts include but are not limited to methadone (thiamethadone), pyriampanel (perampanel), piracetam (piracetam), phenylacetamide (phenacemide), phenylbutyluride (pheneturide), phensumide (phensuximide), phenytoin (phenytoin), potassium bromide (potassium bromide), pregabalin (pregabalin), primidone (primidone), retigabine (retigabine), rufinamide (rufinamide), cetramycin (seletracetam), sodium valproate (sodium valproate), stipulol, sultiazine (sultam), temazepam (temazepam), tiagabine (tiagabine), topiramate (topiramate), trimethadione (trimethadione), pennogamide (valactamide), propioamide (progalimide), nicotinamide (hexenamide), and pharmaceutically acceptable salts thereof.

An aspect of the present invention is an agent for inhibiting the metabolism of fenfluramine, characterized by the formation of desfenfluramine, comprising:

fenfluramine and CYP450 enzyme inhibitors,

wherein the CYP450 enzyme inhibitor down-regulates the formation of desfenfluramine.

Another aspect of the invention is a formulation for use as described above, wherein the patient is diagnosed with a form of refractory epilepsy.

Yet another aspect of the invention is a formulation for use as described above, wherein the refractory epilepsy is in a form selected from the group consisting of delavir syndrome, renox-gares syndrome, dorze syndrome and westster syndrome.

One aspect of the invention is a formulation for suppressing appetite in a subject, the formulation comprising:

a therapeutically effective amount of fenfluramine; and

a CYP inhibitor;

wherein the CYP inhibitor down-regulates the formation of desfenfluramine.

A further aspect of the invention is a formulation for the above use, wherein the CYP inhibitor is a CYP450 inhibitor.

Yet another aspect of the present invention is the formulation for the above use, wherein the CYP450 inhibitor is selected from the group consisting of a CYP1a2 inhibitor, a CYP2B6 inhibitor, a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor and a CYP3a4 inhibitor.

A further aspect of the invention is a formulation for the above use, wherein the inhibitor is selected from the group consisting of stiripentol, oxazepine and cannabidiol.

A further aspect of the invention is a formulation for use as described above, wherein the CYP inhibitor is cannabidiol.

A further aspect of the invention is a formulation for the above use, further comprising an effective amount of an additional agent selected from the group consisting of acetyl amine, barbituron, becloramine, busulfame, bupropion, cilanlan, oxazepam, clonazepam, lorazepam, diazepam, dipropionic acid, eslicarbazepine acetate, dioxidione, ethionin, felbamate, gabapentin, lacosamide, lorazepam, metaphenytoin, methazolamide, mesumamide, mebutamide, mebendazole, midazolam, nimetapam, nitrazepam, oxcarbazepine, metylpyrone, piracetamide, benzoylurea, beflunomide, phensumide, phenytoin, potassium bromide, pregabalin, primisone, retigabine, flutriamide, valsartan, valacil, tiazem, valbutin, valbut, Topiramate, trimethadione, pennogamide, valproamide, vigabatrin, zonisamide, and pharmaceutically acceptable salts thereof.

One aspect of the present invention is a formulation for reducing the therapeutic dose of fenfluramine, said formulation comprising:

fenfluramine; and

the cannabidiol is a compound of the general formula I,

wherein the fenfluramine is used in an amount of at least 20% lower than the therapeutic dose required when treating a patient for the indication to be treated.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine used is reduced by at least 30%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine used is reduced by at least 40%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine used is reduced by at least 50%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine used is reduced by at least 60%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine used is reduced by at least 70%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine administered is reduced by at least 80%.

A further aspect of the present invention is a formulation for the above use, wherein the amount of fenfluramine administered is reduced by at least 90%.

A further aspect of the invention is a formulation for use as described above, wherein the indication for treatment is appetite suppression.

A further aspect of the invention is a formulation for use as described above, wherein the indication for treatment is refractory epilepsy.

Yet another aspect of the invention is a formulation for the above use, wherein the refractory epilepsy is selected from the group consisting of delavir syndrome, renox-garstokes syndrome and dorzelesm syndrome.

One aspect of the invention is a formulation for reducing a therapeutic dose of a first drug, the formulation comprising:

a first drug; and

a second drug which is a CYP450 enzyme inhibitor,

wherein the first drug is administered in an amount at least 20% less than the therapeutic dose required for the indication being treated.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 30%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 40%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 50%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 60%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 70%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 80%.

Yet another aspect of the present invention is a formulation for use as described above, wherein the amount of said first drug used is reduced by at least 90%.

A further aspect of the invention is a formulation for use as described above, wherein the first drug is fenfluramine and the indication for treatment is appetite suppression.

A further aspect of the invention is a formulation for use as described above, wherein the CYP450 enzyme inhibitor is cannabidiol and the indication for treatment is refractory epilepsy.

Yet another aspect of the invention is a formulation for the above use, wherein the refractory epilepsy is selected from the group consisting of delavir syndrome, renox-garstokes syndrome and dorzelesm syndrome.

These and other objects, advantages and features of the present invention will become apparent to those skilled in the art from a reading of the detailed description of the treatment of epilepsy or neurological disorders by co-administration of fenfluramine or a pharmaceutically equivalent salt thereof and one or more metabolic inhibitors, as described more fully below.

Drawings

The invention is best understood from the following detailed description when read with the accompanying drawing figures. It is emphasized that, according to common practice, the various features of the drawings are not to scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. The following figures are included in the drawing.

Figure 1 is a flow chart in tabular form detailing the assessment and plasma sampling over each of the three study periods during the clinical trial detailed in example 1.

Figure 2 consists of two bars showing the effect of co-administration of fenfluramine with stiripentol, valproate and oxazepine on the plasma levels of fenfluramine and desefloramine in healthy patients as described in example 1.

FIG. 3 is a flow chart that graphically represents the development of the physiologically based pharmacokinetic drug-drug interaction (PBPK DDI) model described in example 2.

Figure 4 is a schematic representation of the physiologically based pharmacokinetic drug-drug interaction (PBPKDDI) model described in example 2.

Fig. 5A to 5E are timing diagrams showing changes in plasma levels of analytes for patients administered the following drugs, alone or in combination: fenfluramine (0.8mg/kg), stiripentol (2500mg), oxazepine (20mg), or valproic acid (25mg/kg up to 1500 mg). Figure 5A is a time diagram of the changes in plasma fenfluramine and desfetamine in a subject treated with 0.8mg/kg fenfluramine. Figure 5B is a time diagram showing the changes observed in plasma levels of fenfluramine and desethylfenfluramine in subjects treated with 0.8mg of fenfluramine in combination with 3500mg of setripentol, 20mg of oxazepam and 25mg/kg (to a maximum of 1500mg) valproic acid. In fig. 5A and 5B, the observed data points from the study in example 1 are superimposed on a curve representing the predicted exposure levels of fenfluramine and desfenfluramine generated by running the PBPK DDI model described in example 2. Figure 5C is a timing diagram showing the changes in plasma levels of oxazepine observed in subjects administered oxazepine alone or in combination with fenfluramine. Fig. 5D is a timing diagram showing the changes in plasma levels of stiripentol observed in subjects administered setripentol alone or in combination with fenfluramine. Fig. 5E is a time plot showing the changes in plasma levels of valproic acid observed in subjects administered valproic acid alone or in combination with fenfluramine. In all of fig. 5C, 5D and 5E, the observed data points from the study in example 1 are superimposed on curves representing predicted oxazepam, stiripentol or valproic acid levels, respectively, produced by the PBPK DDI model described in example 2.

FIG. 6 compares the observed effect of fenfluramine co-administration with stiripentol, valproic acid and oxazepine on plasma levels of stiripentol, valproic acid and oxazepine (STP/VPA/CLB AUC)_0-72Percent change) and the effect on each drug predicted by the PBPK DDI model described in example 2.

Figure 7 consists of graphs 7A, 7B, 7C, 7D, 7E and 7F, each showing the values of clearance of specific CYP450 enzymes taking into account renal excretion and liver metabolism, and showing the relative contribution to total clearance based on literature reports and culture studies using human liver microsomes. Clearance values are measured as follows: blank indicates no contribution, + indicates minimum contribution, and + + indicates partial contribution. Based on literature reports and data obtained from in vitro studies and the FDA basic and mechanical Static Models (FDABasic and mechanical Static Models) provided by the inventors, inhibition and induction values reflect the relative intensity of the agent to enzyme activity. Inhibition and induction values were measured as follows: blank indicates no effect, 1 indicates weak effect, and 2 indicates strong effect.

Definition of

As used herein, the term "subject" refers to a mammal. Exemplary mammals include, but are not limited to, humans, domestic animals (e.g., dogs or cats, etc.), farm animals (e.g., cows, sheep, pigs, or horses, etc.), or laboratory animals (e.g., monkeys, rats, mice, rabbits, or guinea pigs, etc.). In certain embodiments, the subject is a human.

As used herein, the terms "treatment" and "treat", "treating" and the like refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects caused by the disease. As used herein, the terms "treat," "treating," "treatment," or "treatment" do not necessarily imply a complete cure or elimination of the disease or disorder, and include inhibition of the formation of potentially harmful drug metabolites. Alleviating any sign or symptom of an undesirable disease or condition to any extent can be considered treatment and/or therapy. In addition, treatment may include acts that may worsen the overall perception of the patient's health or appearance. As used herein, "treatment" covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject susceptible to the disease but not yet diagnosed; (b) inhibiting the disease, i.e. arresting its development; and (c) alleviating, i.e., causing regression of, the disease.

As used herein, the term pKa refers to the negative logarithm (p) of the acid dissociation constant (Ka) of an acid and is equal to the pH at which equal concentrations of the acid and its conjugate base form are present in solution.

As used herein, the term "fenfluramine active agent" refers to an agent that is at least partially a functional equivalent of fenfluramine. In some cases, the fenfluramine active agent is fenfluramine itself, or a pharmaceutically acceptable salt thereof. In some cases, the fenfluramine active agent is a structural derivative of fenfluramine. "structural derivative" refers to a compound that is derived from a similar compound by a chemical reaction. In some cases, the fenfluramine active agent is a structural analog of fenfluramine, i.e., a compound that can be theoretically produced from another compound if one atom or group of atoms is replaced with another atom or group of atoms, whether the compound has been synthesized or can be synthesized by existing methods. In some cases, a fenfluramine active agent may be a structural analog of fenfluramine in which one or more atoms are substituted with an isotope such as deuterium, 15N and 13C.

As used herein, the term "metabolic enzyme" refers to any enzyme or biochemical pathway that converts one molecule to another, whether by chemical modification, conformational change, or noncovalent association with another chemical species. The molecules produced by the action of metabolic enzymes are called "metabolites". Many metabolic enzymes and enzyme systems are known in the art, including but not limited to cytochrome P450 or CYP450 enzyme systems found in the lung, and glucuronyl transferases found in the cytosol.

The term "fenfluramine metabolising enzyme" as used herein refers to any endogenous enzyme that acts in vivo on a fenfluramine or fenfluramine analogue substrate to produce desfetamine or a dealkylated (de-alkylated) fenfluramine-type metabolite. Any suitable inhibitor of these metabolic enzymes may be utilized in the subject methods and compositions to block the metabolism of the fenfluramine active agent.

As used herein, terms such as "unwanted metabolites" and "undesirable metabolites" refer to metabolites that are undesirable for any reason. An "adverse metabolite" is a metabolite associated with one or more adverse reactions. An illustrative example of an adverse metabolite is a dealkylated fenfluramine metabolite such as desfenfluramine, which activates the 5HT-2B receptor and is associated with cardiac valve hypertrophy. In general, harmful metabolites may act through any number of pathways and may be associated with any number of adverse reactions.

As used herein, "clearance" refers to the process of removing a molecule from the body and includes, but is not limited to, biochemical pathways that convert the molecule into its metabolites, as well as renal clearance.

Detailed Description

Before the present methods and compositions are described, it is to be understood that this invention is not limited to particular methods and compositions described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It should be understood that this disclosure supersedes any disclosure of the incorporated publication to the extent contradictory.

It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the method" includes reference to one or more methods and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. In addition, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed for the agents.

SUMMARY

The basic concept behind the present invention is to provide formulations and methods of treatment using compositions of certain drugs in which a first drug with a known benefit is metabolized to a metabolite that has an adverse effect, wherein the first drug is administered with a second drug that inhibits the metabolism of the metabolite that the first drug becomes an adverse effect.

The present invention is based on the unexpected discovery that when certain first drugs of metabolites with adverse effects are co-administered with certain second drugs, the exposure of patients to toxic metabolites is reduced while the exposure to the first drug remains within therapeutic levels. In one exemplary combination, the first drug is a fenfluramine active agent and the second drug is cannabidiol. When fenfluramine is administered in combination with cannabidiol, the formation of desfenfluramine is down-regulated while the plasma concentration of fenfluramine remains within therapeutic levels. In addition to multi-drug combinations comprising fenfluramine and cannabidiol, other embodiments are contemplated and disclosed herein.

The general purpose of the pharmaceutical composition is to make it possible to treat a range of different diseases and conditions in a patient with a first drug, while avoiding the adverse side effects of metabolites of the first drug. It is a further object to provide a combination therapy wherein the second agent enhances the therapeutic efficacy of the first agent. It is a further object to provide combination therapy wherein the second drug provides a therapeutic benefit in addition to the therapeutic effect provided by the first drug.

The methods and multi-drug compositions provided by the present invention and disclosed herein represent an improvement over the prior art, providing the advantage of improved patient safety compared to methods and compositions using only the first drug. Further, certain embodiments of the methods and compositions provided herein allow for reduction in the dosage of the first drug while maintaining efficacy equivalent to that provided by a higher dosage of the first drug when used as monotherapy. Further, certain embodiments of the methods and compositions provided herein allow for increased dosages of the first drug without increasing the safety risks associated with lower dosages of the first drug when used as monotherapy. Further, certain embodiments of the methods and compositions provided herein exhibit improved efficacy relative to methods and compositions using only the first agent. Finally, certain embodiments of the methods and compositions provided herein provide a therapeutic effect in addition to the therapeutic effect of the first agent.

Multi-drug composition

Aspects of the invention provided by the present disclosure include multi-drug compositions in which a first drug having a known therapeutic benefit and metabolized to a metabolite having an adverse reaction is administered with a second drug that inhibits the formation of the metabolite.

Therapeutic agents useful in the multi-pharmaceutical compositions of the present invention include fenfluramine active agents including, but not limited to, fenfluramine and pharmaceutically acceptable salts thereof. Other therapeutic agents including, but not limited to, structural analogs of fenfluramine are also contemplated.

As discussed above and not to be bound by theory, fenfluramine is metabolized into desfenfluramine by cytochrome P450 enzymes including, but not limited to, CYP1a2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3a 4. As discussed above and not to be bound by theory, desfenfluramine is a 5HT2B agonist and may be responsible for adverse cardiac and pulmonary reactions associated with drugs. By and selection ofThe second medicament inhibits the metabolism of fenfluramine into desfenfluramine, which in turn down regulates the production of desfenfluramine. The end result is an increase in AUC of fenfluramine and desfenofluramine in a manner that significantly reduces patient exposure to desfenofluramine while maintaining fenfluramine within therapeutic levels_0-72Ratio of values. Figures 7A and 7B present the contribution of specific enzymes in the total clearance of these compounds.

Accordingly, in one aspect, the present disclosure provides a multi-drug composition wherein fenfluramine is co-administered with a second drug that inhibits the metabolism of fenfluramine to defecafluramine by one or more CYP450 enzymes. In various embodiments, the second agent is one or more of CYP1a2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3a4 inhibitors. In various embodiments, the second drug is an inhibitor of CYP1a 2. In various embodiments, the second drug is an inhibitor of CYP2B 6. In various embodiments, the second drug is an inhibitor of CYP2C 9. In various embodiments, the second drug is an inhibitor of CYP2C 19. In various embodiments, the second drug is an inhibitor of CYP2D 6. In various embodiments, the second drug is an inhibitor of CYP3a 4.

A variety of antiepileptic drugs are inhibitors and inducers of metabolic pathways. The effects of the selected agents are presented in fig. 7C to 7F. Of the antiepileptic drugs, stiripentol and oxazepam are most commonly used to treat delavir syndrome. Stiripentol strongly inhibits CYP1a2 and CYP3a4, and also inhibits CYP2C9 and CYP2C19, although at a lower intensity. Referring to fig. 7C, review of stiripentol based on european public evaluation reports of the european medicines authority (first published in 7.1.2009), Tran et al, ClinPharmacol therm.1997 nov; 62(5) 490-504, and Moreland et al, DrugMetabDispos.1986 Nov-Dec; 14(6) 654-62, which is a weak inhibitor of CYP3A 4. See FDA approved labeling text for an orally administered Onfi (oxazepine) tablet (2011, 10 months and 21 days). Further, there is evidence that oxadiazepine strongly inhibits CYP2D 6. See fig. 7D.

Example 1 describes a clinical trial in healthy volunteers to study the drug-drug interaction between fenfluramine and the antiepileptic drugs, stiripentol, oxazepam and valproate. The results show that co-administration of fenfluramine and the three drugs reduced the patient's exposure to desfetamine by nearly 30% while increasing fenfluramine exposure by 1.67 fold. See fig. 2. These results indicate that fenfluramine exposure to desfetamine can be significantly reduced while maintaining fenfluramine within the normal range by co-administration of fenfluramine and a metabolic inhibitor.

Accordingly, the present disclosure provides multi-pharmaceutical compositions wherein fenfluramine is administered with stiripentol, oxazepam and valproate.

Example 2 describes the development and evaluation of a physiologically-based pharmacokinetic ("PBPK") model for quantifying drug-drug interactions between fenfluramine and stiripentol, oxazepam and valproate. See fig. 3 and 4. The results of the model simulations show that co-administration of fenfluramine with stiripentol alone, with oxazepam alone, and with stiripentol and oxazepam together significantly reduces patient exposure to desfenfluramine. See fig. 6.

Accordingly, the present disclosure provides a multi-drug composition wherein fenfluramine is administered with a second drug selected from the group consisting of stiripentol, oxazepam, and a combination of stiripentol and oxazepam. In an exemplary embodiment, the multi-drug composition comprises fenfluramine co-administered with stiripentol. In an exemplary embodiment, a multi-drug composition comprises fenfluramine co-administered with oxazepam. In an exemplary embodiment, the multi-pharmaceutical composition comprises fenfluramine co-administered with stiripentol and oxazepam.

Recently, cannabidiol has been shown to exert an inhibitory effect on several CYP450 enzymes. It is a potent inhibitor of CYP1a2 (time-dependent effect), CYP2B6 and CYP3a4, and also has an inhibitory effect on CYP2C8, CYP2C9, CYP2C19 and CYP2D 6. See fig. 7F.

Example 3 details a refinement of the PBPK model described in example 2 to provide the ability to mimic the effects of co-administration of fenfluramine with cannabidiol alone or in combination with other drugs (on the effects of fenfluramine and desfetofloxacin exposure in patients co-administered with those drugs the model was assessed by comparing the changes in fenfluramine and desfetofloxacin exposure predicted by the model with those observed in healthy volunteers.

Accordingly, the present disclosure provides a multi-drug composition wherein a first drug is fenfluramine and the first requirement is co-administration with a second drug which is cannabidiol.

The multi-drug compositions disclosed herein may further comprise one or more additional drugs in addition to the first and second drugs. The third or more drugs may be metabolic inhibitors that further inhibit the formation of harmful metabolites from the first drug (therapeutic agent) by the same or different metabolic enzyme or pathway as the second; or the third or more drugs may be agents that provide further therapeutic benefit, for example by enhancing the efficacy of the first drug or providing additional therapeutic benefit; or the third or more drugs may be both metabolic inhibitors and agents that provide further therapeutic benefit. Drugs of interest in this regard include, but are not limited to, acetyl amine, baroxalone, beclomethamine, busulfan, bupropion, cilanlan, oxazepam, clonazepam, lorazepam, diazepam, divalproeic acid, eslicarbazepine acetate, dioxidione, ethionine, feurette, gabapentin, lacosamide, lorazepam, mefentoin, methazolamide, mefenamide, methylphenidate, midazolam, nimetazepam, nitrazepam, oxcarbazepine, metione, piracetam, phenylurea, phenylbutyluride, phenytoin, potassium bromide, pregabalin, pramipedone, retigabine, seletracepam, valproate, depentaploriptan, sulthiazide, temazepam, tiazepam, tiagabine, valprozil, penamide, hexenoamide, hexenoic acid, and the like, Zonisamide and pharmaceutically acceptable salts thereof.

Method of producing a composite material

The present disclosure provides methods wherein a first drug having a known benefit is metabolized to a metabolite that has an adverse reaction, wherein the first drug is administered with a second drug that inhibits formation of the metabolite. Examples of medicaments useful in practicing the present invention are described above.

In one aspect, the present disclosure provides methods of administering a fenfluramine active agent to a subject in need thereof, e.g., for treatment of a host suffering from a disease or condition treatable by a fenfluramine active agent (as described in more detail herein). Another aspect of the methods of the invention is the administration of a fenfluramine active agent to a subject in combination with a second drug that inhibits the formation of desfenfluramine.

In one aspect, the multi-pharmaceutical compositions provided herein are useful for treating patients suffering from or having been diagnosed with a disease or disorder, or experiencing symptoms for which they are in need of treatment, such as patients having been diagnosed with pediatric epileptic encephalopathy, including but not limited to delavir syndrome, renox-gars syndrome, dorzee syndrome, and west syndrome, or patients experiencing pediatric refractory epilepsy, or patients susceptible to sudden epileptic death (SUDEP), or patients diagnosed with alzheimer's disease and obesity. In one aspect, the multi-pharmaceutical compositions provided herein are useful for treating, reducing, or ameliorating the frequency and/or severity of symptoms associated with such diseases or disorders.

"in combination with" or "in combination with" means that an amount of metabolic enzyme inhibitor is administered anywhere before or after fenfluramine active agent is administered simultaneously to about 1 hour or more, e.g., about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, about 6 hours or more, about 7 hours or more, about 8 hours or more, about 9 hours or more, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or more, about 14 hours or more, about 15 hours or more, about 16 hours or more, about 17 hours or more, about 18 hours or more, about 19 hours or more, about 20 hours or more, about 21 hours or more, about 22 hours or more, about 23 hours or more, about or 24 hours or more. That is, in certain embodiments, the fenfluramine active agent and the metabolic enzyme inhibitor are administered sequentially, e.g., the fenfluramine active agent is administered before or after the metabolic enzyme inhibitor. In other embodiments, the fenfluramine active agent and the metabolic enzyme inhibitor are administered simultaneously, e.g., the fenfluramine active agent and the metabolic enzyme inhibitor are administered simultaneously as two separate formulations, or in combination in a single composition that is administered to the subject. Whether the fenfluramine active agent and metabolic enzyme inhibitor are administered sequentially or simultaneously as described above, or any effective variation thereof, for the purposes of the present invention the agents are considered to be administered together or in combination. The route of administration of the two agents may vary, with representative routes of administration described in more detail below.

In embodiments of the invention, any metabolic enzyme may be used in a dose that inhibits the metabolic enzyme inhibitor. The dosage of a particular metabolic inhibitor will generally be within a particular range, but will vary depending on factors including, but not limited to, the age, weight, CYP2C19 metabolic activity, and the presence (presence) and extent of liver damage of the patient. Such doses are less than the daily dose of metabolic enzyme inhibitor that causes undesirable side effects.

Thus, for cannabidiol, a dosage of about 0.5 mg/kg/day to about 25 mg/kg/day may be used, e.g., less than about 0.5 mg/kg/day, about 0.6 mg/kg/day, about 0.7 mg/kg/day, about 0.75 mg/kg/day, about 0.8 mg/kg/day, about 0.9 mg/kg/day, about 1 mg/kg/day, about 2 mg/kg/day, about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 6 mg/kg/day, about 7 mg/kg/day, about 8 mg/kg/day, about 9 mg/kg/day, about 10 mg/kg/day, about 1 mg/kg/day, about 12 mg/kg/day, about 13 mg/kg/day, about 14 mg/kg/day, about 15 mg/kg/day, about 16 mg/kg/day, about 17 mg/kg/day, about 18 mg/kg/day, about 19 mg/kg/day, about 20 mg/kg/day, about 21 mg/kg/day, about 22 mg/kg/day, about 23 mg/kg/day, about 24 mg/kg/day, to about 25 mg/kg/day.

For oxazepine, it is administered according to FDA guidelines, according to initial, dose adjustment (dose titration) and maximum doses depending on the weight, tolerance and response of the patient. Thus, for oxazepine, a dosage of about 5 mg/kg/day to about 40 mg/kg/day may be used, for example about 5 mg/day, about 7.5 mg/day, about 10 mg/day, about 12.5 mg/day, about 15 mg/day, about 17.5 mg/day, about 20 mg/day, about 22.5 mg/day, about 25 mg/day, about 27.5 mg/day, about 30 mg/day, about 32.5 mg/day, about 35 mg/day, about 37.5 mg/day, to about 40 mg/day.

For stiripentol, according to FDA guidelines, the initial dose, dose titration and maximum dose administration are dependent on the weight, tolerance and response of the patient. Thus, for stiripentol, a dosage of about 20 mg/kg/day to about 50 mg/kg/day may be used, such as about 20 mg/kg/day, about 21 mg/kg/day, about 22 mg/kg/day, about 23 mg/kg/day, about 24 mg/kg/day, about 25 mg/kg/day, about 26 mg/kg/day, about 27 mg/kg/day, about 28 mg/kg/day, about 29 mg/kg/day, about 30 mg/kg/day, about 31 mg/kg/day, about 32 mg/kg/day, about 33 mg/kg/day, about 34 mg/kg/day, about 35 mg/kg/day, about 36 mg/kg/day, about 37 mg/kg/day, about, About 38 mg/kg/day, about 39 mg/kg/day, about 40 mg/kg/day, about 41 mg/kg/day, about 42 mg/kg/day, about 43 mg/kg/day, about 44 mg/kg/day, about 45 mg/kg/day, about 46 mg/kg/day, about 47 mg/kg/day, about 48 mg/kg/day, about 49 mg/kg/day, to about 50 mg/kg/day.

As indicated above, the amount of metabolic enzyme inhibitor administered may be based on the body weight of the patient or may be preset to be an amount that will vary with the inhibitor, e.g. expressed in micrograms/day, mg/day or g/day or as a more or less frequently administered dose. Generally, the patient should be administered the minimum dose that is effective in inhibiting the metabolism of the fenfluramine active agent.

Generally, known inhibitors have recommended dosing amounts. These recommended dosage amounts are provided in the latest version of the Physician's Desk Reference (PDR) or http:// emericine. mediscape. com/, both of which are incorporated herein by Reference, particularly with respect to any inhibitor, and more particularly with respect to the recommended dosage amount for these inhibitor drugs.

With respect to the present invention, the inhibitor may be used in the recommended dosage amount or may be used in an amount ranging from about 1/100 to 100 times, or from 1/10 to about 10 times, or from about 1/5 to about 5 times, or from about 1/2 to about 2 times, the recommended dosage amount, or any increment of 1/10 between these ranges.

In some cases, the fenfluramine dose may be determined relative to the dose of co-therapeutic agent administered therewith such that the patient's exposure to fenfluramine is maintained within a therapeutic range while the dose of co-therapeutic agent does not exceed recommended levels and/or minimizes or prevents unwanted side effects known to be associated with co-therapeutic agents. For example, the fenfluramine dose may be calculated based on the molar or weight ratio of fenfluramine to the co-therapeutic agent. When fenfluramine is administered with a co-therapeutic agent, the dosage of fenfluramine can be set according to the lowest dose that provides patient exposure within the therapeutic level. The fenfluramine dose may be set according to the highest dose that provides the patient's exposure to desfenfluramine, which does not exceed the limits set by the FDA or which results in an increased risk that the patient will experience one or more severe adverse effects.

With respect to the present invention, fenfluramine may be used in the dose recommended for fenfluramine in the absence of a co-therapeutic agent, or may be used in an amount ranging from 1/100 to 100-fold, or from 1/10 to about 10-fold, or from about 1/5 to about 5-fold, or from about 1/2 to about 2-fold, or any increment 1/10 between these ranges.

In other words and more specifically fenfluramine can be used for the treatment of patients. For example, fenfluramine may be used in the treatment of patients with epileptic forms such as delaviru's syndrome, renox-gares ' syndrome, dutrex's syndrome, or other refractory epilepsy, and may also be used for appetite suppression. However, in any case where fenfluramine is used, it may be used in combination with an enzyme inhibitor such as cannabidiol, thereby reducing the necessary dosage of fenfluramine in order to obtain therapeutically effective results and substantially reducing the adverse side effects from the reduction of fenfluramine.

The therapeutically effective dose of fenfluramine is reduced when combined with cannabidiol. The reduction in the amount of full therapeutic dose required to achieve the desired therapeutic effect is expected to be about 40% ± 5%. However, when fenfluramine is combined with cannabidiol (each ± 5%), the reduction may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.

This finding of treating patients with a combination of fenfluramine and cannabidiol makes it possible to significantly reduce the dosage of fenfluramine, thereby allowing a wider range of indications for a wider range of patients to be treated with fenfluramine without adverse effects. With this particular combination, cannabidiol inclusion (inclusion) makes it possible to reduce the amount of exposure of a patient to desfenofluramine, which is a metabolite of fenfluramine, and thus to reduce side effects.

Pharmaceutical preparation

Pharmaceutical formulations are also provided. As used herein, a pharmaceutical formulation refers to a composition comprising one or more compounds (alone or in the presence of one or more additional active agents) in a pharmaceutically acceptable vehicle. The term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier with which the compounds of the invention are formulated for administration to a mammal.

The choice of excipients will depend in part on the active ingredient, as well as the particular method used to administer the composition. Thus, there are a variety of suitable formulations of the pharmaceutical compositions of the present invention.

In one aspect, the present disclosure provides a pharmaceutical formulation wherein the active agent is a fenfluramine active agent, i.e. fenfluramine or a pharmaceutically acceptable salt thereof. Dosage forms of fenfluramine active agent for use in the method of the present invention may be prepared by combining the fenfluramine active agent with one or more pharmaceutically acceptable diluents, carriers, adjuvants and the like in a manner known to those skilled in the art of pharmaceutical formulation. Dosage forms of metabolic enzyme inhibitors for use in the methods of the present invention may be prepared by combining the enzyme inhibitor with one or more pharmaceutically acceptable diluents, carriers, adjuvants and the like in a manner known to those skilled in the art of pharmaceutical formulation. In some cases, the dosage form of the fenfluramine active agent and the dosage form of the metabolic enzyme inhibitor are combined in a single composition.

For example, the fenfluramine active agent and/or metabolic enzyme inhibitor may be mixed with conventional pharmaceutically acceptable carriers and excipients (i.e., vehicles) and used in the form of aqueous solutions, oils, oil-based or liquid-based emulsions, tablets, capsules, elixirs (elixirs), suspensions (suspensions), syrups, wafers, powders, and the like. In certain embodiments, such pharmaceutical compositions comprise from about 0.1% to about 90% by weight of fenfluramine active agent and/or metabolic enzyme inhibitor, more typically from about 1% to about 30% by weight of fenfluramine active agent and/or metabolic enzyme inhibitor. The pharmaceutical compositions may contain the usual carriers and excipients for fenfluramine active agents or drugs co-administered with fenfluramine agents, including: carriers suitable for use with water-soluble drugs such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid, as well as carriers and excipients suitable for use with poorly or immiscible water-miscible drugs such as organic solvents, polymers, and the like. Disintegrants commonly used in the formulations of the invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

Certain formulations of the multi-drug compositions disclosed herein are in liquid form. The liquid may be a solution, emulsion, colloid, or suspension, such as an oral solution, emulsion, or syrup. In an exemplary embodiment, the oral solution, emulsion, gel or syrup is included in a bottle with a pipette calibrated to obtain milligrams of solution in a given volume. Liquid dosage forms make it possible to adjust solutions to the child, which can be administered anywhere from 0.1mL to 50mL and in any amount between one-tenth mL increments, thus at 0.1, 0.2, 0.3, 0.4mL, etc.

Liquid compositions will typically consist of a suspension, suspension or solution of the fenfluramine active agent and/or the metabolic enzyme inhibitor or a pharmaceutically acceptable salt in a suitable liquid carrier, e.g. ethanol, glycerol, sorbitol, e.g. polyethylene glycol, oil or water, in a non-aqueous solvent with suspending agents, preservatives, surfactants, wetting agents, flavouring or colouring agents. Alternatively, the liquid formulation may be prepared from a reconstitutable powder.

Particular formulations of the invention are in solid form.

Particular formulations of the invention are in the form of transdermal patches.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric.

Example 1

Drug-drug interaction studies: effect of co-administration of fenfluramine with stiripentol, oxazepine and valproic acid on plasma levels of fenfluramine and desfetiflamne

The effect of co-administration of the three-drug combination regimen on fenfluramine metabolism and the resulting plasma levels of fenfluramine and its metabolite desfetamine was evaluated in clinical trials used in healthy volunteers. Interim results are reported below.

A. Purpose and design of the experiment

A randomized, non-blind (open-label), single dose, three-way crossover study was designed to examine the effect of co-administration of fenfluramine with a three drug mixture consisting of stiripentol, oxazepam and valproic acid. Each patient was treated with three treatment regimens in turn, each treatment regimen being administered separately, according to six different treatment sequences randomly assigned.

Treatment sequence	Period 1	Period 2	Period 3
				1	A	B	C
2	B	C	A
				3	C	A	B
4	C	B	A
				5	A	C	B
6	B	A	C

B. Selection of the subject

Subjects were recruited from an existing pool of volunteers or by direct advertising, with potential subjects (prospects) who participated in the study within three months prior to dosing being excluded from the pool of potential participants. The complete medical history for the first 12 months was obtained from the primary care physician of each subject and evaluated. The patients were then evaluated according to the inclusion and exclusion criteria shown below. The person selected as a study participant had a screening visit prior to participation to reevaluate and confirm compliance with these criteria.

1. Inclusion criteria

1. Healthy men.

2. Healthy women in non-pregnant, non-lactating periods.

3. Ages 18 to 50 years, including 18 and 50 years.

4. Body mass index of 19.0 to 31.0kg/mg²And a minimum body weight of 50.0kg (including 50kg), and the investigator considered clinically insignificant at the time of screening or when out of range.

5. Medically healthy, there is no belief by researchers that clinically significant conditions involved in the study, such as significant renal endocrine, cardiac, mental, gastrointestinal, pulmonary or metabolic disorders, would be excluded. The subject should be free of liver dysfunction.

6. There were no clinically significant abnormalities in their clinical laboratory profile that the investigator believed would exclude study participation, including liver function tests outside the normal range.

7. Non-smokers (including electronic cigarettes and nicotine replacement products) for at least 3 months and tested negative (<10ppm) in the carbon monoxide breath test at screening and admission.

8. The appropriate contraceptive method must be agreed to.

9. Female subjects with non-fertility potential must be surgically infertile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, as determined by the subject's history) or congenital infertile, or at least 2 years post-menopausal. Women with fertility potential must use appropriate contraceptive measures.

10. The english language can be fully spoken, read and understood to complete all research assessments.

11. The subject must voluntarily provide written informed consent.

12. The investigator believes that the subject must be able to complete the study procedure.

13. One must be willing to comply with the requirements and limitations of the study.

Admission criteria 2 and 7 in the above list were re-evaluated before admission/administration.

2. Exclusion criteria

1. A female with fertility potential during pregnancy or lactation.

2. A male subject with a pregnancy partner.

3. Has uncontrolled Blood Pressure (BP), i.e., the subject has a supine systolic blood pressure of greater than 160mmHg or less than 90mmHg and/or a supine diastolic blood pressure of greater than 100mmHg or less than 40mmHg at the time of screening or hospitalization.

4. Oxygen saturation in room air < 92%.

5. Has allergic reaction or specific reaction to fenfluramine, stiripentol, oxapicloram or valproic acid.

C. Evaluation of

An overview of the study procedure is provided in the experimental flow chart presented in fig. 1.

D. Results

The interim results of the drug-drug (DDI) study are shown in fig. 2. AUC calculated based on plasma levels of fenfluramine and desfetiflamine_0-72The value is obtained. Exposure Effect is expressed as AUC determined for patients receiving combination therapy_0-72Values compared to AUC determined for patients receiving fenfluramine alone_0-72The ratio of the values. These results show that when fenfluramine is co-administered with a combination of stiripentol, oxazepam and valproic acid, the patient's exposure to fenfluramine increased 1.66 fold and exposure to desethylfenfluramine decreased 0.59 fold.

Example 2

Development and evaluation of physiologically-based pharmacokinetic ("PBPK") models for prediction of drug-drug interactions

A Physiologically Based Pharmacokinetic (PBPK) model capable of quantifying potential drug-drug interactions (DDI) and facilitating dose rationality of clinical trials of Fenfluramine (FEN) was developed, evaluated and then used to predict the effect of co-administration of one or more anti-epileptic drugs (AEDs), in particular, Setripentol (STP), valproic acid (VPA) and oxapicrin (CLB).

A. Model development

See fig. 3 and 4. The PBPK model for concomitant drugs (comuitant mediations) was developed by refining the PBPK model from published literature; the fenfluramine model was developed de novo using the basic properties of the molecule (non-binding moiety, pKa, etc.). Drug interactions were explained by adjusting the simulated metabolic enzyme efficiency at each simulated time point according to the concomitant drug concentration in the liver at that time point. The PBPK model takes into account age-dependent factors such as blood flow, tissue volume, glomerular filtration rate, CYP maturation, intrinsic liver clearance, and bioavailability. Each model consisted of 10 perfusion-limited tissues.

Calculating tissue-plasma coefficients of FEN and its metabolite desfenfluramine (norFEN) by integrating physiochemical characteristics and in vitro properties such as LogP, pKa and fup; see Xenobiotica (2013)43: 839. Kidney excretion and liver metabolism abolish FEN; intrinsic hepatic Clearance (CL) of 76%_int) Converted to norFEN. See Arch Int PharmacodynTher, (1982)258:15 and J Pharmacy Pharmacol (1967)19: 49S.

The STP PBPK model was developed by a refinement of the published PBPK model in which STP was eliminated only by liver metabolism. See Pharm Res (2015)32: 144. Refinement involves incorporating a secondary elimination pathway for renal clearance into the system. Both CLB and VPA PBPK models were developed through a refinement of previously published models. See Pharm Res (2015)32:144 and Eur J Pharm Sci (2014)63: 45.

For drug-drug interactions, inhibition of FEN elimination by stiripentol and oxazepam is described by reversibly inhibiting CYP1a2, CYP3a4, CYP2C9, CYP2C19 and CYP2D6 mediated hepatic metabolism based on the hepatic concentration of the concomitant drug. Model development was performed in Berkeley Madonna (section 8.3.18).

Intrinsic hepatic clearance (DDI) of FEN in the composition can be calculated as

Wherein the ratio of the sum of fm,_othersIncluding the values of fm and/or fm,_CYP3A4and (f) is,_CYP2C19

B. model evaluation

The model was evaluated by comparing the changes observed in the exposure of fenfluramine and desfenfluramine in the study described in example 1 above with the predicted effect of the model. Figures 5A to 5E show that the predicted changes in plasma levels of fenfluramine, deethylfenfluramine, stiripentol, oxazepam and valproic acid are very small compared to those observed in healthy volunteers, demonstrating the robustness of the model.

C. Effect of co-administration of fenfluramine with one or both of oxazepam and stiripentol on the prediction of plasma levels of fenfluramine and desfetiflamine

The PBPK DDI model was used to predict the effect of co-administration of fenfluramine with one or both of stiripentol and oxapicloram. The results are presented in fig. 6.

Example 3

Extrapolation and refinement of the PBPK model to include the effect of cannabidiol on fenfluramine exposure

The model developed as described in example 2 was further refined to provide the ability to mimic the effect of FEN and Cannabidiol (CBD) administration alone or in combination with other drugs on fenfluramine and desfenofluramine exposure. In particular, the model described in example 2 was modified to explain the inhibitory effect of cannabidiol on the metabolic enzymes that metabolize fenfluramine, namely CYP1a2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3a4, and the time-dependence of the inhibitory effect of CBD on CYP1a 2.

Example 4

Extrapolation and refinement of the PBPK model to include the effect of cannabidiol on fenfluramine exposure

In addition to the substitution of stiripentol and oxazepine with cannabidiol, administered at doses of 10 mg/day and 25 mg/day, respectively, the effect of co-administration of a two-drug combination regimen comprising fenfluramine and cannabidiol on the plasma levels of fenfluramine metabolites and the resulting fenfluramine and its metabolites desfenfluramine was evaluated in clinical trials using healthy volunteers according to the protocol described in example 1. Patients receiving fenfluramine were dosed at 0.2 mg/kg/day or 0.8 g/kg/day.

The foregoing merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements that, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Thus, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention is embodied by the appended claims.

Claims (15)

1. Use of a formulation for inhibiting metabolism of a first drug characterized by formation of metabolites with adverse reactions, the formulation comprising:

the first drug and a second drug in the form of a CYP450 enzyme inhibitor,

wherein the CYP450 enzyme inhibitor down-regulates the formation of the metabolite of the first drug.

2. The use according to claim 1, wherein,

said first agent is characterized by acting on the 5-HT receptor and further by the formation of metabolites with known adverse effects acting on the 5-HT2B receptor; and

the CYP450 enzyme inhibitor down regulates the formation of the metabolite.

3. The use according to claim 1 for preventing, alleviating or ameliorating seizures in a patient diagnosed with a neurological disease.

4. The use of claim 3, wherein the patient is diagnosed with a form of refractory epilepsy.

5. The use of claim 4, wherein the form of refractory epilepsy is selected from the group consisting of Delavir syndrome, Renox-Kastokes syndrome, Duzier syndrome, and Wester syndrome.

6. The use according to claim 1, for suppressing appetite in a subject.

7. Use according to any one of claims 1-6, wherein the first drug is fenfluramine and the detrimental metabolite is desfenfluramine.

8. The use of any one of claims 1-7, wherein the CYP450 inhibitor is selected from the group consisting of a CYP1a2 inhibitor, a CYP2B6 inhibitor, a CYP2C9 inhibitor, a CYP2C19 inhibitor, a CYP2D6 inhibitor, and a CYP3a4 inhibitor.

9. The use of any one of claims 1-8, wherein the CYP450 inhibitor is selected from the group consisting of stiripentol, oxazepine, and cannabidiol.

10. The use according to any one of claims 1-9, wherein the CYP inhibitor is cannabidiol.

11. The use of any one of claims 1-10, wherein the formulation further comprises a co-therapeutic agent selected from the group consisting of acetazolamide, bardoxolone, becloram, busulfan, bupropion, cilanlan, oxazepam, clonazepam, lorazepam, diazepam, divalproex, eslicarbazepine acetate, dioxidione, ethionin, felbamate, gabapentin, lacosamide, lacipam, metaphenytoin, acetomethazolamide, mesufamide, mefenamide, meprobamate, mebendazole, mefenamide, mebendazole, nimetazepam, nitrazepam, oxcarbazepine, methadone, piracetam, phenylacetamide, beflunomide, phenytol, potassium bromide, pregabalin, primisone, retigabine, felbamide, valsartan, valproate, triptylin, valsartan, sumatriptan, temazepam, valbutriptan, valbuterol, sumatriptan, temazepam, valbuterol, valbutin, valbuterol, valbutin, valbut, Tiagabine, topiramate, trimethadione, penoxamide, valproamide, vigabatrin, zonisamide and pharmaceutically acceptable salts thereof.

12. Use of a formulation for reducing the therapeutic dose of fenfluramine, said formulation comprising:

fenfluramine; and

the cannabidiol is a compound of the general formula I,

wherein the fenfluramine is used in an amount of at least 20% lower than the therapeutic dose required when treating a patient for the indication to be treated.

13. Use according to claim 12, wherein the amount of fenfluramine administered is at least 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the therapeutic dose required when treating a patient for the indication being treated.

14. The use of claim 13, wherein the indication being treated is appetite suppression.

15. The method of claim 13, wherein the indication being treated is refractory epilepsy selected from the group consisting of delavir syndrome, renox-garstokes syndrome, and dorzelescent syndrome.