MXPA02004164A - Method and compositions for administering taxanes orally to human patients. - Google Patents

Abstract

Taxane antineoplastic agents which have heretofore exhibited poor or non existent oral bioavailability are administered orally to human patients suffering from taxane responsive disease conditions and made sufficiently bioavailable to achieve therapeutic blood levels. In a preferred embodiment, the taxane, preferably paclitaxel, is co administered to the patient with an oral cyclosporin enhancing agent, preferably cyclosporin A. By one preferred method, a dose of oral enhancer is administered about 0.5 72 hours before the taxane and a second dose of the enhancer and administered immediately before, together with or immediately after the taxane. A method of treating human patients suffering from taxane responsive disease conditions is also provided, as well as a method for providing such treatment while preventing or reducing hypersensitivity and allergic reactions without the need for pre medication.

Description

METHOD AND COMPOSITIONS TO ADMINISTER TAXANES VIA ORAL TO HUMAN PATIENTS FIELD OF THE INVENTION The invention relates to methods and compositions for orally administering to human patients compounds that are difficult to absorb from the gastrointestinal tract, and to methods for the treatment of patients by oral administration of these compounds. More specifically, the present invention relates to methods and compositions for the oral administration of paclitaxel, and related taxanes, to humans.

BACKGROUND OF THE INVENTION Very valuable pharmacological active compounds can not be administered effectively orally to human patients due to poor or inconsistent systemic absorption of the gastrointestinal tract. All these pharmaceutical compounds, therefore, are generally administered intravenously, requiring the intervention of a physician or other health care professionals, implying considerable discomfort and potential local trauma to the patient and even requiring administration in a facility hospital with surgical access in the case of certain intravenous infusions (iv).

One of the important classes of cytotoxic compounds that are normally bioavailable when administered orally to humans are taxanes, which include paclitaxel, its derivatives and analogues. Paclitaxel (currently marketed as TAXOL® by Bristol-Mayers Squibb Oncology Division) is a natural diterpene product isolated from the Pacific yew tree (Taxus brevifolia). It is a member of the taxane family of terpenes. It was first isolated in 1971 by Ani et al., (J. Am. Chem. Soc., 93: 2325, 1971), who characterized its structure by chemical and crystallographic methods by X-ray. A mechanism for its activity is referred to to the ability of paclitaxel to bind to tubulin, thereby inhibiting the growth of cancer cells. Schiff et al., Proc. Nati Acad. Sci. USA; 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kuman, J. Biol. Chem., 256: 10435-10441 (1981).

Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intern. Med., 111 : 213, 1989). It is effective for chemotherapy for various types of neoplasm including breast (Holmes 5 et al., J. Nat Cancer Inst., 83: 1797, 1991) and has been approved for the treatment of breast cancer as well. It is a potential candidate for the treatment of neoplasms that skin, lung cancer and carcinomas of the head and neck (Forastire et al., Sem. Oncol., 20: 56, 10 1990). The compound also shows potential for the treatment of polycystic kidney disease (Oo et al., Nature, 368: 750, 1994) and malaria.

The poor solubility of paclitaxel in water has created 15 important problems in the development of convenient injectable and infusion formulations, useful for cancer chemotherapy. To improve the solubility of paclitaxel in aqueous solutions, some paclitaxel compositions formulated for IV infusion 20 have included CREMOPHOR® EL (a product of the condensation of polyethoxylated castor oil and ethylene oxide marketed by BASF). For example, paclitaxel used in clinical trials under the auspices of the National Cancer Institute (NCI) has been 25 formulated in 50% CREMOPHOR® EL and 50% alcohol - Tirri rriiiiíiTirfnriM [• - - »- * dehydrated. CREMOPHOR® EL has been shown to be toxic and produces vasodilation, difficult breathing, lethargy, hypotension and death in dogs after IV administration. It is also considered to cause allergic-type or hypersensitivity reactions. There is also evidence that paclitaxel causes acute hypersensitivity reactions in the absence of CREMOPHOR® EL.

Paclitaxel analogues derived at the 2 'and / or 7 positions have been synthesized with groups that improve water solubility. These actions have produced prodrug compounds that are more water soluble than the parent compound and that show the cytotoxic properties with activation. A major group of these prodrugs includes the 2 '-oxon salts of paclitaxel and docetaxel, particularly the 2'-methylpyridinium mesylate salts (2'-MPM).

Studies in animals have shown that paclitaxel is very difficult to absorb when administered by (less than 1%). See Eiseman, et al., Second NCI orkshop on Taxol Science and Applications (CRC Press nineteen ninety five). Eiseman, et al., Indicate that paclitaxel has a bioavailability of 0% with oral administration, and Suffness, et al., Report that oral dosing with paclitaxel was not possible because no evidence of antitumor activity was found with oral administration of up to 160 mg / kg / day.

PCT application WO 95/20980 (published August 10, 1995), Benet, et al., Discloses a proposed method for increasing the bioavailability of hydrophobic pharmaceutical compositions administered orally. This method consists of orally administering such compounds to the patient concurrently with a biomeder which consists of an inhibitor of a cytochrome P450 3A enzyme or a membrane transport inhibitor mediated by P-glycoprotein. Benet et al., However, provide virtually no means to identify that bioavailability enhancing agents will improve the availability of specific "target" pharmaceutical compounds, nor do they indicate specific dosage amounts, schedules or schedules for the administration of enhancing agents. or objective Benet lists various potential enhancers (P450 3A inhibitors) and target drugs (substrates of P450 3A) but the only combination of the enhancer and the objective agent exemplified in terms of experimental evidence is ketoconazole as the enhancer and cyclosporin A as the target drug.

Thus, there remains a need for methods for the administration of taxanes, for example, paclitaxel, which are cytotoxic compounds, which are safe and effective and particularly methods that reduce the adverse reactions associated with parenteral administration of paclitaxel and various solubilizers and excipients such as CREMOPHOR® EL.

SUMMARY OF THE INVENTION An aspect of the present invention is directed to a method for reducing the incidence or severity of hypersensitivity reactions associated with the parenteral administration of a taxane. The method comprises the oral administration of a formulation of 15 taxane, where the formulation causes hypersensitivity reactions when administered orally. In preferred embodiments, the taxane is selected from the group that paclitaxel, docetaxel, a derivative, analog or prodrug of paclitaxel or docetaxel, for example, 20 paclitaxel-2'MPM and docetaxel-2'-MPM, 2'MPM salts of the taxane and these polymorphs and hydrates. It is preferred that the taxane be present in the formulation in an amount from about 60 mg / m to about 250 mg / m. 25 i -? ffifttitg-ftmm * if * - * - «» * »- Applicants have also discovered that the intestine is practically impermeable to CREMOPHOR® EL administered orally. That is, Cremophor is not transported through the intestinal epithelium to achieve detectable concentrations in blood. Accordingly, another aspect of the present invention is directed to a method for selectively improving the bioavailability of a pharmaceutical active compound. The method includes orally co-administering to a human a bioavailability enhancing compound and a formulation that includes an active pharmaceutical compound and at least one solvent. Preferred bioavailability-enhancing compounds include cyclosporins AZ dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833 and SDZ-NIM 811. The pharmaceutical compound reaches therapeutic concentrations in blood but the solvent tending to cause adverse side reactions such as hypersensitivity does not achieve active concentrations in blood. In the preferred embodiments, the pharmaceutical compound is a taxane and the solvent is a polyalkoxylated castor oil such as CREMOPHOR® EL. In the most preferred embodiments, CREMOPHOR is present in the formulation in an amount from about 3 to 10 mg / mL.

Another aspect of the present invention is directed to a composition containing a taxane and a polyalkoxylated castor oil (optimally including an excipient) in the form of an oral dosage unit.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the circulating concentrations of paclitaxel in samples taken: (a) bottom curve - for a period of 6-8 hours from a group of rats administered alone with oral paclitaxel, and (b) ) upper curve - during a 24 hour period of a second group of rats administered orally one hour before the co-administration of oral cyclosporin A and oral paclitaxel.

Figure 2 is a graph showing the concentrations of paclitaxel in plasma samples of a human patient administered oral paclitaxel after two doses of oral cyclosporin A, the first administered one hour before the paclitaxel dose and the second administered immediately after the paclitaxel.

Figure 3 is a graph showing the concentrations of paclitaxel in plasma samples of a t ^^ Au second human patient administered oral paclitaxel by the same scheme as described with respect to Figure 2.

Figure 4 is a graph showing a comparison of the paclitaxel plasma concentration curves determined for 24 hours in rats (Figure 1) and in humans (Figures 2 and 3) administered with oral paclitaxel after two doses of oral cyclosporin A .

Figure 5 is a table showing the treatment program of paclitaxel and oral cyclosporin used in Example 5.

Figure 6 is a table showing haematological toxicity after oral administration of paclitaxel, described in Example 5.

Figures 7A and 7B are tables showing the non-haematological toxicity after oral administration of paclitaxel, described in Example 5.

Figure 8 is a table showing the pharmacokinetics of oral paclitaxel described in Example 5.

Figure 9 is a table showing the pharmacokinetics of CsA described in Example 5.

Figure 10 is a graph showing the area under 5 cuurva (AUC, uM.h)) of oral paclitaxel against dose DETAILED DESCRIPTION OF THE INVENTION A first aspect of the present invention proposes 10 a method to prevent or reduce hypersensitivity and allergic reactions in human patients receiving taxane treatment. The method consists in the oral administration of the taxane to the patients. The oral administration by the currently described method is 15 much less likely to produce such adverse reactions compared to intravenous therapy. Applicants administered paclitaxel to human patients (see Examples 2 and 3) without premedication (for example without H-1 H-2 blockers or steroids). The Therapeutic circulating concentrations of paclitaxel were obtained and no hypersensitivity reactions were observed.

Applicants have discovered that taxanes, which have been considered characterized by profiles of Therapeutically inadequate oral absorption can be administered orally to humans with sufficient systemic absorption and oral bioavailability obtained to present plasma concentrations in the therapeutic range.The term "bioavailability" when used in this refers to the systemic availability (i.e., blood / plasma concentrations) of a certain amount of the drug administered to a patient.The applicants have actually administered the taxane paclitaxel orally to human patients suffering from cancers and have verified that therapeutic blood concentrations of paclitaxel were achieved in these patients for prolonged periods of time.

In a preferred embodiment, the taxane is coadministered with an absorption enhancing or bioavailability enhancing agent to a human patient "co-administration" of the enhancing agent comprises practically simultaneous administration with the taxane (less than 0.5 hours before, less than 0.5 hours later or together), from about 0.5 to about 72 hours before administration of the taxane, or both, ie, with one or more doses of the same or different improving agent given at least 0.5 hours before and one dose provided practically at the same time with (together with or immediately before or after) the taxane. In addition, "co-administration" comprises administering more than one taxane dose for 72 hours after a dose of the enhancing agent, in other words, the enhancing agent (s) need not be administered another before or with each taxane administration, but may be administered intermittently during the course of treatment.

Orally administered orally-enhancing agents useful in the practice of the preferred embodiment of the invention include, but are not limited to, cyclosporins, including cyclosporin A to Z, but particularly cyclosporin A (cyclosporin), cyclosporin F, cyclosporin D , dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833, and SDZ-NIM 811, ie, ((Mel-4-cyclosporine, a non-immunosuppressive, antiviral cyclosporine) (both available from Novartis Pharmaceutical Corp). The structures of cyclosporins A-Z are described in Table 1 below.

TABLE 1 Cyclosporins A-Z ga¡ttaitatÉit-- »^ t-fí-¿., Mm. L.m .. ~ m.- ~ m-ll¡li¡ / f.-1á ~. * .- ~. »Tfejfctt»? The cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of approximately 1200 and showing immunosuppressive properties. These are produced by members of the genus Topycladium, including, for example, Topycladium infla tum Gams (formerly known as Trichoderma polysporum), Topycladium terrapin and other imperfect fungi. The main component is cyclosporin A, also known as cyclosporin or CsA, some other minor metabolites, including cyclosporin B to Z, have been found to have substantially less immunosuppressive activity than cyclosporin A, or in some cases, without immunosuppressive activity. These are used intravenously or orally as immunosuppressants, mainly for organ transplantation and some other conditions. Cyclosporins, particularly cyclosporin A, are known inhibitors of the glycoprotein P efflux pump and other transport pumps as well as certain cytochrome P 450 degradative enzymes, but to date no effective scheme has been developed to apply this property in the clinic to the point of clinical and commercial possibility or regulatory approval. Some synthetic and semi-synthetic analogues have been prepared. See generally, Jegorov et al., Phytochemistry 38: 403-407 (1995). The natural, semi-synthetic and synthetic analogs of the cyclosporins can be used in the practice of the present invention.

It is possible to choose cyclosporine without taking into account whether it presents immunosuppressive activity in vivo. One of the surprising discoveries of the invention is that the immunosuppression observed with certain cyclosporins is inexplicably linked to the improvement in oral bioavailability of the therapeutic compounds. Thus, cyclosporin F improves the oral bioavailability of paclitaxel even though it has been reported that it does not show immunosuppressive activity. Stewart, et al., Transplantion Proceedings 200 (Supp.3): 989-992 (1998); Granelli- Piperno, et al., Transplantion 46: 53S-60S (1988).

Without pretending to adhere to any specific theory regarding functioning, a possible explanation for the increase in the observed bioavailability of paclitaxel is that there is interaction at the level of the enzymes that metabolize the drug for cyclosporins and paclitaxel. It is known that both compounds are highly metabolized by the cytochrome P450 system (for example, P-450 3A which is concentrated in the liver as well as in the *"*--*- -"- -*- *-* small intestine. It is possible that cyclosporin administered before the taxane inhibits these enzymes so that paclitaxel, which is non-polar and lipophilic, is absorbed. In the absence of this local inhibition, paclitaxel is metabolized to more polar metabolites that cross the mucosa.

This theory of inhibition of intestinal metabolism of the target compound could have little or no effect on the increase in systemic blood concentrations when the target compounds are administered intravenously. Moreover, since the primary effect of the oral absorption enhancing agent may be a local effect on the intestinal lumen, doses that are sub-therapeutic (for example in terms of immunosuppression) must be effective in obtaining the desired object. This is an important consideration in the case of enhancing agents such as cyclosporins that have a powerful immunosuppressive activity and may present toxicity problems if administered at high dose concentrations. Thus, the observation of applicants that non-immunosuppressive cyclosporins, such as cyclosporin F, can still function as an oral enhancer is of great clinical value.

The term "taxane" includes but is not limited to paclitaxel, paclitaxel analogs such as docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl paclitaxel), derivatives, analogs and prodrugs of paclitaxel and docetaxel, for example salts such as the salts paclitaxel-2 '-methylpyridinium (MPM) and docetaxel-2' -MPM, taxane 2'-MPM and polymorphs and hydrates thereof. The dosage range of the taxane target agents administered orally may vary from one compound to another based on their therapeutic index, the requirements of the condition being treated, the condition of the patient and others. The method of the invention makes it possible to administer paclitaxel and other taxanes orally in a range from about 20 mg / m to about 1000 mg / m (based on the patient's body surface area) or about 2-30. mg / kg (based on the body weight of the patient) as individual or divided daily doses (2-4) and maintain plasma concentrations of paclitaxel in humans in the range of 50-500 ng / mL for prolonged periods (for example 8 -12 hours) after each oral dose. These concentrations are at least comparable with those obtained with the treatment of taxol by IV infusion of 96 hours (which causes great inconvenience, discomfort, loss of qualitative time, potential of infections, etc., in the patient). In addition, these plasma concentrations of paclitaxel are more than sufficient to provide the desired pharmacological activities of the target drug, for example, the inhibition of tubulin disassembly (occurring at concentrations of approximately 0.1 μM, or approximately 85 ng / mL) and the inhibition of protein isoprenylation (occurring at concentrations of approximately 0.03 μM or close to 25 ng / mL) that are directly related to its antitumor effects by inhibiting oncogenic functions and other signal transducing proteins that play a major role in the regulation of cell growth. The tumor does not distinguish how the anti-cancer drug is administered.

The preferred oral dose amounts for paclitaxel and other taxanes used according to the invention are about 60-250 mg / m or about 2-6 mg / kg. It may be convenient in some cases to administer to the patient a higher initial loading dose of the target compound to obtain peak blood concentrations, followed by lower maintenance doses.

The dose range of the enhancer compound co-administered with the taxane according to the invention is ,. approximately 0.1 to about 20 mg / kg of the patient's body weight. Two or more different enhancer compounds and / or two or more different target compounds can be administered together, alternately or intermittently in all the different aspects of the method of the invention.

The present invention can be used to treat • human patients affected with cancers, tumors, Kaposi's sarcoma, malignancies, tissue proliferation or 10 uncontrolled cell secondary to tissue injury, and any other disease state that responds to the taxanes. Among the types of carcinoma that can be treated particularly effectively are hepatocellular carcinoma and liver metastasis, cancers of the tract 15 gastrointestinal, pancreas, prostate and lung and Kaposi's sarcoma. Examples of non-cancerous disease states that can be effectively treated with these orally administered active compounds according to the present invention are tissue or cell proliferation.

Uncontrolled cell secondary to tissue injury, polycystic renopathy, inflammatory diseases (eg arthritis) and malaria, including malaria parasites resistant to chloroquine and pyrimethamine. See, Pouvelle, et al., J. Clin. Invest. 44: 413-417 (1994). 25 * ~~ * - ** mm *? mimiA ^. ». t.?.*M*~..- ... - ... m ^ ..... .. ^^ r ^. ... ...,., - r • - ~~~ ~ ~ * The invention is particularly useful in the treatment of patients with primary tumors and metastases. The active ingredient penetrates the intestinal wall as a result of the co-administration of the cyclosporin improver and is rapidly captured by the circulation by such, providing a higher initial local concentration of the chemotherapeutic compound in the liver. This local concentration may, in fact, be greater than the concentration currently obtained with IV infusion treatment). The higher concentrations of paclitaxel in the liver after oral administration may not be manifested in the increased plasma concentrations due to the high effect of the first step in the liver. The method of the invention, for the selective production of high concentrations in blood of the antitumor compounds, is particularly valuable in the treatment of liver cancers (for example hepatocellular carcinoma and liver metastasis), gastrointestinal cancers (eg, colon, rectal), and lung cancers.

It is emphasized that this aspect of the present invention does not require any specific bioavailability enhancing agent. Nor is it limited to any ^^^^ * ¿> ^^^^^ quantity or specific dosage scheme. In less preferred embodiments, the taxane is administered without a bioavailability enhancing agent.

Another aspect of the present invention is directed to a composition containing a taxane in the form of an oral dosage unit. The dosage unit • may be in the form of tablets, capsules (soft gelatin or hard gelatin), dragees, gelcaps, 10 pills, liquids (for example solutions, suspensions or elixirs), powders pills, micronized particles or usual osmotic substrate systems and any other oral dosage form known in the art • Pharmaceutical In the preferred modalities, the unit of The dosage is in the form of a liquid and includes paclitaxel or another taxane in a vehicle comprising CREMOPHOR® EL or another polyalkoxylated castor oil (for example a polyethoxylated castor oil), alcohol and / or a polyoxyethylated sorbitan monooleate (for example). example 20 TWEEN® 80, ICI Americas, Inc.), transcutol and optionally a flavoring. Each dosage unit includes an effective amount of a taxane and a carrier, the carrier can contain one or more of the following ingredients, namely, carriers, fillers, binders or 25 excipients, disintegrators, solvents, sweeteners, tl < - > * A «. * JU-l > .... - * "frf» »-. r ..,.» mm., ....,.,. ^ ..,... "," »...". < - » <tb> <tb> <tb> dyeing agents and any other inert ingredients that are normally included in pharmaceutical dosage forms for oral administration See Remington's Pharmaceutical Sciences, 17th edition, (1985).

The precise amounts of each taxane in the oral dosage forms will vary depending on the age, weight, disease and condition of the patient. For example, paclitaxel or other taxane dosage forms may contain sufficient amounts of the target agent to provide a daily dosage of about 20-1000 mg / m (based on the patient's body surface area) or about 2-30 mg / kg. mg / kg (based on the patient's body weight) is individual or divided daily doses (2-3). Preferred dosage amounts are about 50-200 mg / m or about 2-6 mg / kg.

Dosage schedules will also vary depending on factors such as patient characteristics and disease status. Preferred dosage schemes for the administration of oral paclitaxel are: (a) daily administration to a patient in need of these 1-4 equally divided doses providing about 20-1000 mg / m (based on the surface area of the body), and preferably about 50-200 mg / m, with continuous daily administration for 1-4 consecutive days every 2-4 weeks, or (b) administration of approximately one day each week. The first program is comparable to the use of paclitaxel infusion for 96 hours every 2-3 weeks, which is considered a preferred IV treatment regimen.

The oral administration of the taxanes according to the invention actually decreases the toxic side effects in many cases when compared to the currently used IV treatments. Without intending to adhere to the theory, the applicants consider that contrary to the IV infusion that produces a sudden and rapid high concentration in blood concentrations [sic], oral administration results in absorption of the active compound through the intestinal wall ( favored by the improving agents), a more gradual appearance in blood levels and stable, steady-state maintenance of these levels at or near the ideal interval for a prolonged time.

The plasma concentrations of taxanes administered according to the preferred embodiments of the present invention are remarkably and surprisingly similar to the concentrations observed after IV administration. A series of studies with experimental animals showed that steady state plasma concentrations of paclitaxel were achieved with oral co-administration with CsA by the third day of the scheme. The concentrations of the target compound acquired at steady state were comparable to those achieved in patients by IV infusion of 96-hour paclitaxel. A response rate of 27% was found in patients with metastatic breast cancer treated with a continuous infusion for 96 hours every three weeks (Siedman et al., J. Clin. Oncol., 14: 1877, 1996) who had previously failed with taxane infusions for three hours (taxol or taxotene). It is possible to achieve comparable blood level results with the treatment methods of the present invention without the discomfort, inconvenience and risks of prolonged IV infusions.

The data shown in Figures 1-4 are especially valuable in view of the surprising nature of the results. As described in more detail in the examples set forth below, the data reflected in Figure 1 was generated from studies of administration of paclitaxel to rats, but the data reflects in Figures 2 and 3 actual concentration levels of paclitaxel over time in the plasma of two human patients who were administered oral paclitaxel according to the present invention, ie, with the co-administration of an oral cyclosporin enhancing agent. The data in humans • they are notable not only because they reflect for the first time, as it is found in the literature, that 10 paclitaxel was administered orally to humans requiring paclitaxel treatment, but also because plasma concentrations were obtained at therapeutic level and maintained for approximately a period of 10 hours; actually, the level of The drug observed in the plasma of human patients was comparable with the levels achieved with IV administration and the methods used did not give rise to serious local and systemic side effects. In addition, it should be noted that the concentrations The plasma concentrations are a reflection of the concentration of l ^ k paclitaxel in tissue.

It has now been shown that the rat pharmacokinetic profile of paclitaxel co-administered with cyclosporin A 25 oral is very comparable with the profile in human patients who receive the same scheme. In fact, Figure 4 reflects an overlay on the same graph of the plasma concentration curves for paclitaxel for a period of 24 hours after the oral co-administration of two doses of the enhancer (cyclosporin A) in a space of one hour. with oral paclitaxel administered after the second dose of the enhancer (cyclosporin A) in a space of one hour with oral paclitaxel administered after the second dose of the enhancer, with the data obtained from the study in rats during 24 hours as shown in Figure 1 and studies in human patients as shown in Figures 2 and 3. It can be seen that the three curves of the graph in Figure 4 (one in rat and two in humans) are of similar configuration, indicating that the results in humans are consistent with the results in animal tests.

The rat is an accepted model for evaluating the pharmacokinetic and absorption profiles of chemotherapeutic agents. However, it is also well established that animal results are not predictive of human outcomes due to well-known species-to-species variations. Thus, no clinician or clinician would have administered to humans paclitaxel or other taxanes orally with reasonable confidence only on the basis of data in animals without any clinical experience in humans. In addition, it is very unlikely that doctors will experiment with 5 medications in life-threatening conditions, that is, cancer, when data are not available. The present invention, therefore, teaches a method by • which taxanes can be administered orally in a safe and effective way to humans. From the point of In view of a physician, the current invention is a great improvement over the prior art because it allows the utilization of the beneficial properties of a taxane such as paclitaxel without the need for intravenous catheters and consumption of time in a hospital or clinic. 15 of chemotherapy, as well as the availability of a clinician and the expense of care, inconvenience and risk of infection for the patient, premeditation to avoid hypersensitivity or allergic reactions and potential adverse effects of their own 20 premedications.

• The use of paclitaxel is associated with a variety of toxicities and side effects. Two of the most important toxicities are neutropenia and neutropathy. Various 25 clinical data have shown that it would be desirable to maintain circulating plasma concentrations without a certain "window" to maximize antitumor activity and minimize side effects, especially neutropenia. For many tumor types it is considered that the low, but long-term exposure of tumor cells in the body results in better clinical outcomes. Thus, it would be expected that plasma concentrations of approximately 0.03 micromolar would block cell division. There are clinical data that show that constant intravenous administration for several days to achieve a "window" of approximately 0.05 to 0.1 micromolar in the circulation can minimize toxicities and cause tumor regressions, sometimes even in patients whose tumors did not respond to schemes of infusion for three hours. The currently approved three-hour infusion schedules of paclitaxel achieve maximum plasma concentrations that greatly exceed these concentrations.

The present invention makes it possible to provide paclitaxel in comparatively infrequent daily doses (for example, approximately twice a day) according to programs that would otherwise not be possible or practical with the intravenous route. The use of the enhancer (e.g. cyclosporin A) favors oral absorption of paclitaxel with the first dose and if a second dose of paclitaxel is provided later in the day, the use of additional cyclosporin A even 5 may be unnecessary. Thus, paclitaxel can be provided intermittently as an individual dose in a fixed schedule (per week, biweekly, etc.) or • chronic, for a period of consecutive days (for example 4 days) every 2-4 weeks with the purpose of maintaining the levels within the "window" of safety and efficacy and reducing the toxicities described above.

Another aspect of the invention is directed to a method • to selectively improve the bioavailability of a 15 taxane or other pharmaceutical agent. The method consists in the oral co-administration to a patient of a bioavailability enhancing agent and a formulation containing the pharmaceutical agent and a solvent. The pharmaceutical agent achieves blood concentrations 20 therapeutics but the solvent is not absorbed. Due to its physical and chemical properties, paclitaxel has been normally dissolved in Cremophor for IV administration. The speculation has been that Cremophor is responsible for some allergic type reactions experienced by 25 patients receiving paclitaxel treatment. As ffiWflBBiHftlMMilii? ft 1 i *** * «~» ~ fr it- "T- 'result, patients are premedicated to avoid or reduce hypersensitivity reactions Paclitaxel should be provided slowly to patients, with medical personnel in a constant state surveillance of severe hypersensitivity reactions For normal intravenous regimens, pre-medication regimens of Hl and H-2 blockers plus steroids are usually required.

Applicants have discovered that oral coadministration of a bioavailability enhancing agent and a taxane formulation containing the taxane, CREMOPHOR® EL and ethanol gives rise to the taxane uptake to obtain pharmacologically effective or therapeutic blood concentrations without appreciable blood concentration that Cremophor to cause adverse side effects. Accordingly, this aspect of the present invention encompasses the use of any pharmaceutical agent that is soluble in the solvent such as polyalkoxylated castor oil which tends to cause adverse side effects such as hypersensitivity reactions when administered parenterally. The enhancing agent facilitates the uptake or absorption of the pharmaceutically active agent through the intestine but does not exert this action with respect to the solvent.

The taxanes are preferred active agents. Other agents include anti-neoplastic drugs such as chemotherapeutic agents (e.g., etoposide, camptothecin, CPT-11 (Pharmacia / UpJohn), doxorubicin, vincristine, davnorubicin, mitoxantrone and colchicine), and ganciclovir • and foscarnet. In preferred embodiments, fixed amounts of the bioavailability enhancing agent and the agent Pharmaceutically active agents are formulated together in an oral dosage form in combination. These dosage forms may consist of tablets, capsules, dragees, gelcaps, pills, liquids or pills. A • product in combination as these include from 15 about 0.1 to about 20 mg / kg of one or more cyclosporins A, D, C, F and G, dihydro CsA, dihydro CsC and acetyl CsA together with about 20 to about 20,000 mg / m (based on average surface area) of the patient's body), and Preference is given to about 50-200 mg / m of paclitaxel, docetaxel, other taxanes or derivatives of paclitaxel or docetaxel such as paclitaxel 2'-MPM or docetaxel 2'-MPM.

In other preferred embodiments, the solvent contains a polyalkoxylated castor oil such as CREMOPHOR® EL in an amount from about 3 mg / mL to about 10 mg / mL.

In the case of pharmaceutically active agents that exhibit anti-neoplastic activity, coadministration of the enhancing agent improves on-site activity highly protected by MDR, e.g., testes and brain. Thus, the present invention facilitates the treatment of brain tumors such as glioblastoma multiforme.

In still other preferred embodiments, the enhancing agent or combination of enhancing agents is co-administered with the target agent or a combination of 15 the target agents 10 minutes before, at the same time with and up to two (2) hours after the administration of the target agent (s). In this mode, it is possible to administer an amount of about 30 mg / kg of the patient's body weight. The following examples illustrate some aspects of the invention and demonstrate the unexpected, very substantial increase in oral absorption achieved from paclitaxel. These examples are not proposed, however, for 25 limit the invention in any way or to establish Improvement agents or specific targets, dosing ranges, test procedures or other parameters that can be used exclusively to practice the invention.

EXAMPLE 1 Six (6) healthy Sprague Dawley rats, all weighing from 225-275 grams and approximately 6 to 8 weeks of age, received a single oral dose of paclitaxel at a concentration of 9 mg / kg. Blood samples were collected from the vein of the tail of each rat at 0.5, 1, 2, 3, 4 and 6 hours after the paclitaxel dose. The individual samples were centrifuged and the serum was separated. For each time interval, the six samples were composed to produce a single representative sample. All samples were tested for paclitaxel without change by LC / MS with a lower limit of quantification of 50 pg / mL.

The results of the study are shown in a graph in the lower curve of Figure 1, which indicates that the bioavailability of paclitaxel administered orally in serum was less than 1%.

EXAMPLE 2 Ten (10) healthy Sprague Dawley rats with the same characteristics as those used in the study described 5 in Example 1 were treated with 5 mg / kg of oral cyclosporin A followed then with another dose of 5 mg / kg of oral cyclosporin A and 9 mg / kg of paclitaxel • oral . 10 Blood samples were collected from the tail vein of each rat at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 and 24 hours after the administration of paclitaxel. After proper treatment of the • samples and the creation of a composite sample for the 15 group, the plasma of each sample was tested for paclitaxel without change.

The results of this study are shown graphically in the upper curve of Figure 1. 20 can observe that the paclitaxel plasma concentrations in this group of animals was several times higher during the first six hours compared to the rats of Example 1 that received only paclitaxel, that the levels at or above the concentrations 25"target" therapies were maintained for eight (8) after dosing and significant plasma concentrations were maintained throughout the 24-hour period. 5 EXAMPLE 3 A 71-year-old man with prostate cancer for 3 years agreed to receive an oral dose of paclitaxel and an improver in the form of cyclosporin A. • Your 10 body surface area was 2.04 square meters and its weight was approximately 84 kg. After an overnight fast, he received two doses of cyclosporin A (Sandimmune 5 mg / kg) one hour apart. Shortly after the second dose, the patient drank a dose 15 of paclitaxel in Cremophor / alcohol-based solution containing 180 mg dissolved in 120 mL of 5% dextrose in water, ie, approximately 2.0 mg / kg of body weight or approximately 90 mg / m of body area. No normal premedications were provided, such as those 20 would be used for infusion of short-term taxanes. After drinking the solution, the patient observed that the taste was unpleasant. He experienced some loose stools for a few hours. I also report hot flushes several hours after dosing that could have 25 have been related to the temporary cessation of their Anti-hypertensive medication. In addition to these data, his clinical course was normal.

Plasma samples were obtained at frequent intervals after administration of paclitaxel and were evaluated by LC / MS / MS. The results of the plasma concentration with time are shown in Figure 2. The peak was reached approximately 4 hours after dosing and concentrations above 0.07 micromolar were obtained from about 1 to 5 hours. Concentrations comparable to those found in patients with breast cancer receiving intravenous infusions of 96 hours of paclitaxel (0.05 micromolar) were present for approximately 10-12 hours (Seidman et al., J. Clin. Oncol. 14: 1877, nineteen ninety six).

EXAMPLE 4 A 75-year-old man with prostate cancer for some years received an oral dose of paclitaxel and cyclosporin A. His body surface area was 1.82 square meters and his weight was approximately 72 kg. After fasting overnight, he received the same scheme of cyclosporin A (Sandimmune 5 mg / kg) and oral paclitaxel (180 mg) as the patient of Example 1, which was equal to approximately 2.5 mg / kg or approximately 100 mg / m of paclitaxel in this patient. Again, normal premedications were not provided, as would be used for infusion of short-term taxanes. After drinking the solution, the patient observed that the taste was unpleasant. He experienced some loose stools for a few hours. He also had a slight decline in blood pressure after dosing which had been related to a vaso-vagal reaction secondary to his fasting state and blood draws. As a precaution, the patient received approximately 100 mL of saline intravenously. After eating breakfast he felt much better and the rest of his clinical course was otherwise normal.

Plasma samples were obtained at frequent intervals after administration of paclitaxel and were assessed by LC / MS / MS. The results of the plasma concentrations with time are shown in Figure 3. The maximum concentration was almost 0.3 micromolar and occurred at four hours after dosing. Concentrations above 0.07 micromolar were achieved from about 1 to 10 hours. Again, concentrations comparable to those found in patients with breast cancer receiving intravenous infusions of 96 hours of paclitaxel were present for approximately 12-15 hours.

Figure 4 represents a composite of the levels of paclitaxel concentrations determined over time in rats (upper curve of Figure 1) and in humans (curves of Figures 2 and 3) after oral administration of paclitaxel and two doses of oral cyclosporine with one hour of separation, according to the present invention.

EXAMPLE 5 Fifty-three (53) human patients with incurable malignancies received oral paclitaxel in combination with CsA on one occasion and intravenous paclitaxel (i.v.) at a dose of 175 mg / m as a three-hour infusion on another occasion. The oral formulation and i.v. of paclitaxel consisted of 6 mg / mL of paclitaxel, dissolved in CREMOPHOR® EL and ethanol 1: 1 p / v. Patients received one of 9 dose levels. (See Figure 5) Dose levels 1 and 2 were randomized for oral and i.v. At all major levels (3-9), patients received oral paclitaxel during course 1 and IV paclitaxel during course 2. 5 Prior to administration of oral paclitaxel, patients received oral doses of CsA. The patients received one of the 10 dose levels (Figure 5). At dose levels 2-3, patients received a 10 oral CsA solution 10 minutes before receiving oral paclitaxel. At subsequent doses, CsA was administered in capsules 30 minutes before the administration of paclitaxel. At a dose level 4, CsA was administered 10 minutes before and two hours after the 15 oral paclitaxel administration.

To prevent hypersensitivity, patients were premedicated with dexamethazone 20 mg orally, 12 and 6 hours before i.v. and oral 20 paclitaxel, Clemastine 2 mg i.v. and cimetidine 300 mg i.v. 30 minutes before i.v. administration and oral paclitaxel. Three patients at dose level 8 and all patients at dose level 9 did not receive the aforementioned premedication before administration 25 of oral paclitaxel because no CREMOPHOR® was detected - ~ - »» "Éia? Fta« Mjt ^ í.imjá-, EL in plasma of patients treated at lower doses of paclitaxel To prevent nausea and vomiting, patients at dose levels 8 and 9 were provided with granisertron (Kytril®) 1 mg orally one hour before receiving CsA.

The levels of paclitaxel in urine and plasma were determined using a validated assay by high performance liquid chromatography (HPLC). CsA levels were determined from whole blood samples using fluorescence polarization immunoassay. The ethanol levels were measured from the plasma using a gas chromatograph. The levels of CREMOPHOR® EL were determined using validated HPLC.

The area under the concentration-time curve (AUC) was estimated by the trapezoidal rule with extrapolation to infinity using the K-terminal velocity constant. The terminal half-life (tl / 2) was calculated as 0.693 / k. Other parameters evaluated were the maximum concentration (Cmax), the time for the maximum concentration (Tmax) and the time elapsed above the threshold concentrations of 0.05 μM and 0.1 μM (T> 0.05 μM, T> 0.1 μM). The Cmax and the Tmax were determined by the graphic medium. T > 0.05 μM, and T > 0.1 μM were determined using linear logarithmic interpolation. The percentage of the dose of the recovered administration (Uexcr) was calculated as the amount excreted in the urine divided by the dose of the actual administration multiplied by 100%. Statistical analysis of the data was performed using the Stundent T test and • Pearson's correlation coefficient. A P value of less than 0.05 was considered to have statistical significance.

The main types of haematological toxicity after oral administration of paclitaxel were leukopenia and granulocytopenia (Figure 6). 15 toxicities were of short duration and often pre-existing. The non-haematological toxicities after oral administration of paclitaxel, shown in Figures 7A and 7B were nausea, vomiting, arthralgia / myalgia, and were generally moderate. Any of the Severe toxicities were of short duration and uncomplicated. No toxicities commonly associated with CsA were observed.

The pharmacokinetic parameters of the oral administration of paclitaxel are defined in Figure 8.

- - MniMillliMtl II I ll - I I i 2 2 dose escalation of oral paclitaxel from 60 mg / m to 120 mg / m in combination with CsA 15 mg / kg gave rise to a significant increase in AUC and T > 0.1 μM paclitaxel. Average values of the AUC for the doses of 60 mg / m and 120 mg / m2 were 1.65 +/- 0.93 μM / h and 2.55 +/- 2.29 μM / h, respectively, and the average T > 0.1 μM were 3.7 +/- 2.3 h and 7.9 +/- 8.0 h, respectively. Further increase in the dose of oral paclitaxel did not result in an average significant additional increase in AUC or T > 0.1 μM paclitaxel. The increase in the dose of CsA or the dispersion of the dose did not cause another increase in AUC and T > 0.1 μM paclitaxel compared to the single dose of 15 mg / kg. A large interpatient variability was observed at all dose levels.

The pharmacokinetic parameters of CsA are defined in Figure 9. The increase in the dose and the CsA program gave rise to higher AUC values of CsA, but did not increase the Cmax values. The escalation of the paclitaxel dose did not produce important differences in the pharmacokinetics of CsA. The levels of CREMOPHOR® EL in plasma after oral administration of paclitaxel were not detectable at all paclitaxel dose levels (< 0.01% v / v).

The pharmacokinetic data of paclitaxel IV were in agreement with the results previously observed.

In summary, CREMOPHOR® EL, which can induce hypersensitivity in patients, is not absorbed through the intestine when administered orally as a solvent for paclitaxel. In addition, CREMOPHOR® EL may interfere with the absorption of paclitaxel thus limiting the bioavailability of this medication. He did not observe hypersensitivity in patients who did not receive premeditation before oral administration of paclitaxel. Therefore, paclitaxel can be administered orally without the consequence of hypersensitivity. In addition, the maximum effect of CsA on the improvement of paclitaxel exposure was observed in a single dose of CsA of 15 mg / kg.

In view of the fact that it is possible to carry out some embodiments of the invention mentioned above and it is possible to make various changes in the established modalities, it should be understood that everything described herein must be interpreted in the illustrative sense and not as limiting. t ^ ', ^, tM * "

Claims (22)

1. A method to reduce the incidence or severity of hypersensitivity actions associated with parenteral administration of a taxane, is to orally administer to a patient a formulation containing a taxane, wherein the formulation causes hypersensitivity reactions when administered via parenteral

2. The method of claim 1, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, 2'MPM taxane salts and polymorphs and hydrates thereof.

3. The method of claim 1 wherein the taxane consists of a derivative, analog or prodrug of paclitaxel or docetaxel.

4. The method of claim 3, wherein the prodrug is paclitaxel-2 'MPM or docetaxel 2' -MPM.

5. The method of claim 1, wherein the taxane is paclitaxel or docetaxel.

The method of claim 1, wherein the taxane is present in the formulation in an amount from about 60 to about 250 mg / l. m2.

7. A method for selectively improving the bioavailability of a pharmaceutically active agent, consists of: administering orally to a patient a bioavailability enhancing agent and a formulation that includes a pharmaceutically active agent and at least one solvent that achieves active levels in blood when is administered parenterally, wherein the pharmaceutically active agent achieves the therapeutic levels in blood but the solvent does not reach the active levels in blood.

8. The method of claim 7, wherein the solvent consists of a polyalkoxylated castor oil.

9. The method of claim 8, wherein the formulation further comprises ethanol.

10. The method of claim 7, wherein the bioavailability enhancing agent is selected from the group consisting of cyclosporins A to Z, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833 and SDZ-NIM 811.

11. The method of claim 10, wherein the bioavailability enhancing agent is cyclosporin A.

• The method of claim 7, wherein the bioavailability enhancing agent is administered 10 orally before oral administration of the taxane formulation.

13. The method of claim 7, wherein the • bioavailability enhancing agent is administered 15 orally after oral administration of the taxane formulation.

14. The method of claim 1, wherein the bioavailability enhancing agent is administered 20 orally, practically at the same time with the oral administration of the taxane formulation.

15. The method of claim 7, wherein the bioavailability enhancing agent is administered 25 orally in a time from about one l?.? ? ? m?. ^ ** m mi. ? r * * l * mmm. hour before until approximately two hours after oral administration of the taxane formulation.

16. The method of claim 7, wherein the pharmaceutically active agent is a taxane.

17. The method of claim 16, wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, taxane-2'-MPM salts, and polymorphs and hydrates thereof.

18. The method of claim 16, wherein the taxane comprises a derivative, analog or prodrug of paclitaxel or docetaxel.

19. The method of claim 18, wherein the prodrug is paclitaxel-2'-MPM or docetaxel-2'-MPM.

20. The method of claim 16, wherein the taxane is paclitaxel or docetaxel.

21. The method of claim 16, wherein the taxane is present in the formulation in an amount from about 60 to about 250 mg / m2.

22. A composition containing a taxane and a polyalkoxylated castor oil, wherein the composition is in the form of an oral dosage unit. 5 F li li llffl-IIMllllMil ¡í • - - --- - -