SK5822002A3 - 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

Technical field

The present invention relates to methods and compositions for oral administration, to pharmaceutical compositions that are poorly absorbed from the gastrointestinal tract, to humans, and to methods of treating patients by oral administration of such agents. In particular, the present invention relates to methods and compositions for oral administration of paclitaxel and related taxanes to humans.

BACKGROUND OF THE INVENTION

Many valuable pharmacologically active compounds cannot be effectively administered orally to human patients because they exhibit poor or inconsistent systemic absorption from the gastrointestinal tract. All of these pharmaceutical formulations are therefore generally administered by intravenous routes, requiring the intervention of a physician or other healthcare professional, causing considerable discomfort and possible local trauma to the patient and even requiring hospital administration, with the availability of surgery for some intravenous (iv ) infusions.

One important class of cytotoxic agents that are normally not biologically useful when administered orally to humans is taxanes, which include paclitaxel, its derivatives and anaags. Paclitaxel (currently marketed as TAXOL® from Bristol-Meyers Squibb Oncology Division) is a natural diterpene preparation isolated from the West American yew (Taxus brevifolia). He is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al., (Am. Chem. Soc., 93, 2325, 1971), who characterized its structure using chemical and structural crystallographic methods. One mechanism for determining its activity relates to the capacity of paclitaxel to bind tubulin, while inhibiting the growth of cancer cells. Schiff et al., Proc. Natl. Acad. Sci. USA 77: 1561-1565 (1980); Schiff et al., Nature, 277. 665-677 (1979); Kuman, J. Biol. Chem., 256, 10435-10441 (1981).

Paclitaxel has been approved for clinical use in the treatment of difficult to treat ovarian cancer in the United States (Markman et al., Yale Journal

-2of Biology and Medicine, 64, 583 (1991); McGuire et al., Ann. Intern. Med., 111, 273 (1989). It is effective for use in chemotherapy in some types of neoplasms, including breast tumors (Holmes et al., J. Nat. Cancer Inst., 83, 1797, 1991) and has also been approved for the treatment of breast cancer. It is a potential candidate for the treatment of skin tumors, lung and head cancer, and cervical cancers (Forastire et al., Sem. Oncol., 20, 56, 1990). The compound also has the potential to treat polycystic kidney disease (Woo et al., Nature, 368, 750, 1994) and malaria.

The poor water solubility of paclitaxel caused serious problems in the development of suitable injectable and infusion preparations useful in anticancer chemotherapy. To improve the solubility of paclitaxel in aqueous solutions, some paclitaxel compositions formulated for intravenous infusion include CREMOPHOR® EL (a condensation product of polyethoxylated castor oil and ethylene oxide, commercially available from BASF). For example, paclitaxel used in clinical trials under the auspices of the National Cancer Institute (NCI) was formulated in 50% CREMOPHOR® EL and 50% dehydrated alcohol. CREMOPHOR® EL has been shown to be toxic and produces vasodilation, difficulty breathing, lethargy, hypotension and death in dogs after intravenous administration. It is believed to cause allergic-type reactions or hypersensitivity. There is also evidence that paclitaxel alone induces acute hypersensitivity reactions in the absence of CREMOPHOR® EL.

Paclitaxel analogs were derivatized at the 2 'and / or 7 positions with groups that increase water solubility. In these experiments, precursors of compounds that are more water-soluble than the starting compound and which upon activation exhibit cytotoxic properties were obtained. One significant group of such precursors includes the 2-onium salts of paclitaxel and docetaxel, in particular the 2'-methylpyridinium mesylate (2-MPM) salt.

Animal studies have shown that paclitaxel is very poorly absorbed when administered orally (less than 1%). See Eiseman et al., Second NCI Workshop on Taxol and Taxus (Sept. 1992); Suffness et al., In Taxol Science and Applications (CRC Press 1995). Eiseman et al. report that paclitaxel has a bioavailability of 0% after oral administration and Suffness et al. indicate that oral

-3dosing with paclitaxel does not appear to be possible because no evidence of antitumor activity has been found after oral administration up to 160 mg / kg / day,

In International Patent Application WO 95/20980 (published August 10, 1995) Benet et al. disclose an alleged method of increasing the bioavailability of orally administered hydrophobic pharmaceutical compounds. The method comprises orally administering such compounds to a patient concurrently with a biological enhancer comprising a cytochrome P450 3A enzyme inhibitor or a Pglycoprotein-mediated membrane transport inhibitor. Benet et al. however, they did not actually provide any means of identifying which bioavailability enhancers would improve the availability of specific target pharmaceutical compounds, nor did they provide specific dosage amounts, schedules, or regimens for the administration of enhancer or target agents. Benet reports dozens of potential potentiating agents (P450 3A inhibitors) and target drugs (P450 3A substrates), but the combination of enhancer and target agent, which is exemplified as experimental evidence, is only ketoconazole as enhancer and cyclosporin A as the target drug.

Thus, there remains a need for a method of administering taxanes, such as paclitaxel, which are cytotoxic compounds that are safe and effective, and in particular to have a method that reduces adverse reactions associated with parenteral administration of paclitaxel and various solubilizers and excipients such as CREMOPHOR® EL.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to a method of reducing the incidence and severity of hypersensitivity reactions associated with parenteral administration of a taxane. The method comprises oral administration of a taxane preparation, wherein the preparation causes hypersensitivity reactions when administered parenterally. In preferred embodiments, the taxane is selected from the group consisting of paclitaxel, docetaxel, a derivative, analog or prodrug of paclitaxel or docetaxel, for example, paclitaxel-2'-MPM and docetaxel-2'-MPM, taxane-2'-MPM salts, and polymorphic and hydrates thereof. Preferably, the taxane is present in the formulation in an amount of from about 60 mg / m ² to about 250 mg / m ² .

Applicants have also found that the intestine is substantially impermeable to orally administered CREMOPHOR® EL. This means that cremophor is not transported through the intestinal epithelium to achieve detectable blood levels. Accordingly, another aspect of the present invention is directed to a method for selectively enhancing the bioavailability of pharmaceutical active agents. The method allows the oral co-administration of a human bioavailability enhancer and a composition comprising a pharmaceutically active agent and at least one solvent. Preferred bioavailability enhancing agents are cyclosporins AZ, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833 and SDZ-NIM 811. The pharmaceutical composition reaches therapeutic blood levels, but a solvent which tends to cause adverse side reactions such as hypersensitivity, such as hypersensitivity effective blood levels. In preferred embodiments, the pharmaceutical composition is a taxane and the solvent is a polyalkoxylated castor oil such as CREMOPHOR® EL. In particularly preferred embodiments, CREMOPHOR is present in the formulation in an amount of from about 3 to about 10 mg / ml.

A further aspect of the present invention relates to a composition comprising a taxane and a polyalkoxylated castor oil (optimally comprising an excipient) in the form of an oral dosage unit.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph depicting circulating levels of paclitaxel in samples taken: (a) lower curve - within 6-8 hours from one group of rats receiving oral paclitaxel only; and (b) upper curve - within 24 hours of the other group rats administered orally one hour prior to co-administration of oral cyclosporin A and oral paclitaxel.

Fig. 2 is a graph depicting paclitaxel levels in plasma samples from one human patient receiving oral paclitaxel following two doses of oral cyclosporin A, the first administered one hour prior to the paclitaxel dose and the second administered immediately prior to paclitaxel.

-5Obr. 3 is a graph showing paclitaxel levels in plasma samples from a second patient receiving oral paclitaxel using the same regimen as described in connection with FIG. Second

Fig. 4 is a graph depicting a comparison of paclitaxel plasma levels curves over 24 hours in rats (Fig. 1) and humans (Figs. 2 and 3) receiving oral paclitaxel after two doses of oral cyclosporin A.

Fig. 5 is a table showing the treatment schedule of oral paclitaxel and cyclosporine used in Example 5.

Fig. 6 is a table depicting the haematological toxicity following oral administration of paclitaxel described in Example 5.

7A and 7B are tables showing non-haemological toxicity following the oral administration of paclitaxel described in Example 5.

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

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

Fig. 10 is a graph depicting the area under the curve (AUC, (μΜh)) of oral paclitaxel versus dose (mg / m ² ).

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to a method for preventing or reducing hypersensitivity and allergic reactions in human patients receiving taxane therapy. The method comprises oral administration of a taxane to a patient. It is much less likely that the oral administration of the present invention will produce adverse reactions such as intravenous therapy. Applicants administered paclitaxel to human patients (see Examples 2 and 3) without any pretreatment (for example, without the administration of H-1 H-2 blockers or steroids). Therapeutic circulating levels of paclitaxel were achieved with no hypersensitivity reactions observed.

Applicants have found that taxanes believed to have therapeutically inadequate oral absorption profiles can be administered orally to humans with sufficient systemic absorption and oral bioavailability, reaching plasma levels that are within the therapeutic range. The term bioavailability, as used herein, means systemic utility (i.e., blood / plasma levels) of said amount of drug to be administered to a patient. Applicants have recently administered paclitaxel taxane orally to human cancer patients and confirmed that therapeutic blood levels of paclitaxel in these patients were reached over an extended period of time.

In a preferred embodiment, the taxane is administered to human patients together with an absorption or bioavailability enhancing agent. By co-administration of the enhancer is meant to be administered substantially concurrently with the taxane (either less than 0.5 hours before, not less than 0.5 hours after or together), from about 0.5 to about 72 hours before taxane administration, or both. i.e., with one or more doses of the same or different enhancers administered at least 0.5 hours before and one dose administered substantially concurrently with (either with or immediately before or after) the taxane. In addition, co-administration means administering more than one dose of taxane within 72 hours of the dose of enhancer, in other words, it is not necessary for the enhancer agent (s) to be re-administered before or with each taxane administration, but may be administered alternately. during treatment.

Orally administered enhancers which are useful in a practical preferred embodiment of the present invention include, but are not limited to, cyclosporins which include cyclosporins A to Z, but especially cyclosporin A (cyclosporin), cyclosporin F, cyclosporin D, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833 and SDZNIM 811, ie, ((Me-lle-4) -cyclosporin, antiviral, non-immunosuppressive cyclosporin) (both available from Novartis Pharmaceutical Corp). The structures of cyclosporins A to Z are described in Table 1 below.

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The cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of approximately 1200, and thus exhibit immunosuppressive properties. They are produced by members of the genus Topycladium, including, for example, Topycladium inflatum Gams (formerly referred to as Trichoderma polysporum), Topycladium terricola, and other imperfect fungi. The major component is cyclosporin A, also referred to as cyclosporin or CsA. Some other less important metabolites, including cyclosporins B to Z, have been found to exhibit significantly less immunosuppressive activity than cyclosporin A, or in some cases no immunosuppressive activity. They are used intravenously or orally as immunosuppressive agents, primarily in organ transplantation and in some other cases. Cyclosporins, especially cyclosporin A, are known inhibitors of the P-glycoprotein efflux pump and other transporter pumps. as well as some cytochrome P450 degradation enzymes, but to date no effective regimens have been developed for appropriate clinical introduction in terms of clinical and commercial feasibility or regulatory acceptance. A variety of synthetic and semi-synthetic analogs were prepared. See Jegorov et al., Phytochemistry 38, 403-407 (1995). In practice, natural, semi-synthetic and synthetic cyclosporin analogs can be used in the practice of the present invention.

Cyclosporin may be selected regardless of whether it exhibits immunosuppressive activity in vivo. One surprising discovery of the invention is that the immunosuppression observed with certain cyclosporins is not ultimately associated with an improvement in the oral bioavailability of therapeutic agents. Thus, cyclosporin F increases the oral bioavailability of paclitaxel even though, as noted, it does not exhibit immunosuppressive activity. Stewart et al., Transplantation Proceedings 20 (Suppl. 3), 989-992 (1998); Granelli-Pipemo et al., Transplantation 46, 53S-60S (1988).

Without wishing to be bound by any particular theory regarding the effect, a possible explanation for the observed increased bioavailability of paclitaxel is that there is an interaction at the level of drug metabolizing enzymes for cyclosporin and paclitaxel. Both agents are known to be extensively metabolized through the cytochrome P-450 system (e.g., P-450 3A), which is concentrated in both the liver and the small intestine. It can be assumed that

-10cyclosporin, administered before the taxane, inhibits these enzymes by absorbing paclitaxel, which is nonpolar and lipophilic. In the absence of this local inhibition, paclitaxel is metabolized to more polar metabolites that do not cross the mucosa.

This theory of inhibiting the intestinal metabolism of the target agent could have little or no effect in increasing systemic blood levels when the target agent is administered intravenously. In addition, since the primary effect of oral, absorption enhancing agent may have a local effect in the intestinal lumen, doses that are sub-therapeutic (e.g., as regards immunosuppression) could be effective to achieve the desired effect. This is an important consideration in the case of enhancing agents such as cyclosporins, which exhibit potent immunosuppressive activity and can cause toxicity problems when administered at high dose levels. Thus, the observations of the applicants that non-immunosuppressive cyclosporins such as cyclosporin F may nevertheless act as an oral enhancer are of great clinical importance.

The term taxane includes, but is not limited to, paclitaxel, paclitaxel analogs such as docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetylpaclitaxel), derivatives, analogs and precursors of paclitaxel and docetaxel, for example, salts such as paclitaxel. 2'-methylpyridinium (MPM) and docetaxel-2'-MPM, taxane-2-ΜΡΜ salts and polymorphs and hydrates thereof. The dosage range of orally administered taxane targeting agents will vary from compound to compound, based on its therapeutic index, the requirements of the condition being treated, the condition of the patient, and the like. The method of the present invention allows the administration of paclitaxel and other taxanes orally in the range of about 20 mg / m ² to about 1000 mg / m ² (based on the patient's body surface area) or about 2 to 30 mg / kg (based on the patient's body weight) as a single dose or divided (2-4) daily doses and maintain paclitaxel plasma levels in humans ranging from 50 to 500 ng / ml for an extended period of time (e.g., 8 to 12 hours) after each oral dose. These levels are at least comparable to those achieved with a 96-hour intravenous infusion when treated with taxol (causing considerable discomfort, discomfort, time loss, possible infection, and the like) to the patient. In addition, such plasma levels of paclitaxel are more than sufficient to provide the desired pharmacological activities of the target drug, e.g.

- 11 inhibition of tubulin degradation (which occurs at levels of about 0.1 μΜ or about 85 ng / ml) and inhibition of protein isoprenylation (which occurs at levels of about 0.03 μΜ or about 25 ng / ml) that are directly related to its anti-tumor effects by inhibiting oncogenic functions and other signal-transducing proteins, which play a key role in regulating cell growth. In a tumor, it is not important how the antitumor agent is administered.

Preferred dosage amounts for paclitaxel and other taxanes administered according to the present invention are about 60 to 250 mg / m ² or about 2 to 6 mg / kg. In some cases, it may be appropriate to administer a higher initial dose of the target agent to the patient in order to achieve maximum blood levels followed by lower maintenance doses.

The dosage range of the enhancer, which is co-administered with a taxane within the meaning of the present invention, is about 0.1 to about 20 mg / kg of the patient's body weight. Two or more different enhancing agents and / or two or more different targeting agents may be administered together, alternately or intermittently, in all different aspects of the method of the present invention.

The present invention may be used to treat human patients to ¹ l with cancer, tumors, Kaposi's sarcoma, malignancies, uncontrolled tissue or cellular proliferation secondary to proliferation, tissue injury, and any other disease conditions responsive to taxanes. Types of cancers that can be particularly effectively treated include hepatocellular carcinoma and liver metastasis, cancer of the gastrointestinal tract, pancreas, prostate and lung, and Kaposi's sarcoma. Examples of non-cancerous conditions that can be effectively treated with these orally administered active agents are uncontrolled tissue proliferation or cell proliferation secondary to tissue damage, polycystic kidney disease, inflammatory diseases (e.g., arthritis) and malaria, including malaria-resistant malaria parasites chorochine and pyrimethamine. See Pouvelle et al., J. Clin. Invest. 44, 413-417 (1994).

The present invention is particularly useful in the treatment of patients with primary tumors and metastases. The active ingredient penetrates through the intestinal wall as a result of co-administration of a cyclosporin enhancer and is rapidly absorbed through the portal blood run, providing a higher local initial concentration of the chemotherapeutic agent in the liver. This local concentration may in fact be higher than the concentration currently achieved with intravenous infusion therapy). Higher levels of paclitaxel in the liver following oral administration may not be reflected in elevated plasma levels due to the high effect of the first pass to the liver. The method of the present invention is selectively producing high concentrations of anti-tumor agents in the blood, particularly valuable in the treatment of liver cancer (such as hepatocellular carcinoma and liver metastasis), gastrointestinal tract cancer (such as colon, rectum) and lung cancer.

It should be noted that this aspect of the present invention does not require any particular bioavailability enhancing agent. Nor is it limited to any specific dosage amounts or regimens. In less preferred embodiments, the taxanes are administered without a bioavailability enhancing agent.

I ¹

Another aspect of the present invention relates to a composition comprising a taxane in the form of an oral dosage unit. The dosage unit may be in the form of conventional tablets, capsules (soft gelatin or hard gelatin), capsules, goal tablets, pills, liquid preparations (for example, solutions, suspensions or elixirs), powders, lozenges, micronized particulate or osmotic delivery systems and any other oral dosage forms known in the pharmaceutical art. In preferred embodiments, the dosage unit is in the form of a liquid and comprises paclitaxel, or other taxane, in an adjuvant comprising CREMOPHOR® EL or other polyalkoxylated castor oil (e.g. polyethoxylated castor oil), alcohol and / or polyoxyethylated sorbitan monooleate (e.g. TWEEN® 80, ICI Americas, Inc.), transcutol and optionally an aromatic agent. Each dosage unit contains an effective amount of a taxane and a carrier. The carrier may comprise one or more

13 more of the following ingredients, such as excipients, fillers, binders or excipients, disintegrants, solvents, sweeteners, coloring agents and any other inert ingredients which are usually included in pharmaceutical dosage forms for oral administration. See Remington's Pharmaceutical Sciences, 17 ^th Edition (1985).

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

Dosage schedules will also vary depending on factors such as patient characteristics and disease status. Preferred dosage schedules for administration of oral paclitaxel are (a) daily administration to a patient in need thereof, 1 to 4 equally divided doses providing about 20 to 1000 mg / m ² (based on the patient's body surface area) and preferably about 50 to 200 mg / m ² , with daily administration being continued for 1 to 4 consecutive days of 2 to 3 weeks each, or (b) administration for approximately one day each week. The foregoing schedule is comparable to the use of a 96-hour infusion of paclitaxel every 2-3 weeks, which some consider an intravenous treatment regimen to be preferred.

Indeed, the oral administration of the taxanes of the present invention reduces toxic side effects in many cases, as determined by comparison with currently used intravenous therapies. Without intending to be bound by theory, the Applicants believe that, as opposed to intravenous infusion, which provides sudden and rapid and steep high blood levels, orally results in the active agent being absorbed through the intestinal wall (supported by enhancing agents). ), gradual manifestation of blood levels and stable, steady maintenance of these levels at or near an ideal range over a long period of time.

The levels of plasma taxanes that are administered in accordance with the preferred embodiments of the present invention are remarkably and surprisingly similar to those observed following intravenous administration. A series of studies with experimental animals have shown that steady-state plasma levels of paclitaxel were achieved after oral co-administration with CsA on the third day of the regimen. The steady-state levels of the target agent were comparable to those achieved in patients with a 96-hour intravenous infusion of paclitaxel. A response rate of 27% was found in breast cancer patients with metastases who had been treated with a continuous 96-hour infusion every three weeks (Siedman et al., J. Clin Oncol., 14, 1877, 1996) who had previously failed 3- hourly infusion of taxane (taxol or taxotene). Comparable blood level results can be achieved by the treatments of the present invention, without discomfort, without the hassles and risks of prolonged intravenous infusions.

The data shown in Figures 1 to 4 are particularly remarkable in view of the surprising nature of the results. As described in more detail in the examples below, the data shown in Figure 1 was obtained from paclitaxel administration studies in rats, but the data shown in Figures 2 and 3 depict the actual time levels of paclitaxel plasma concentrations for two human patients receiving oral paclitaxel in accordance with with the present invention, i together with the administration of an oral cyclosporin enhancer. Human data is not insignificant because it reflects, for the first time, to the extent reported in the literature, that paclitaxel was orally administered to people in need of paclitaxel treatment, but also because plasma concentrations of therapeutic levels were reached and maintained throughout about a 10-hour period; indeed, the drug levels found in the plasma of human patients were comparable to those achieved following intravenous administration and the methods used did not cause severe local or systemic side effects. In addition, it should be noted that plasma levels reflect the tissue concentration of paclitaxel.

Thus, the pharmacokinetic profile of paclitaxel co-administered with oral cyclosporin A was demonstrated to be fully comparable in rats to that of human patients who had the same regimen. Indeed, Figure 4 shows

- 15 copying the same plasma concentration curve graph for paclitaxel over a 24-hour period after oral co-administration of two doses of enhancer (cyclosporin A) separated by one hour, with oral paclitaxel administered after the second dose of enhancer (cyclosporin A); data are derived from the 24-hour rat study shown in Figure 1 and the human patient studies shown in Figures 2 and 3. It can be seen that the three curves in the graph of Figure 4 (one for rats and two for humans) they have a very similar shape, indicating that the results obtained in human studies are identical to those obtained in animal tests.

The rat is an accepted model for assessing the pharmacokinetic and absorption profiles of chemotherapeutic agents. It is also well established, but these animal results are not predictive of human results due to the known variation from species to species. Thus, no clinical or general practitioner would administer paclitaxel or other taxanes orally to humans, relying only on the data obtained in animal experiments alone, without any clinical experience in human studies. In addition, physicians are unlikely to experiment with drugs in life-threatening conditions, i. in cancer if data are not available. Accordingly, the present invention provides a method in which taxanes can be safely and effectively administered orally to humans. From the physician's point of view, the present invention is a tremendous improvement over the prior art since it allows the beneficial properties of taxanes such as paclitaxel to be exploited without the need for intravenous catheters and hospital time or chemotherapy clinics, as well as the availability of the clinic and associated costs. and the risk of infection for the patient, the preconditions to prevent hypersensitivity or allergic reactions and the possible adverse effects of the preconditions themselves.

The use of paclitaxel is associated with various toxicities and side effects. The two most prominent toxicities are neutropenia and neuropathy. Many clinical data have shown that it is desirable to maintain plasma circulation concentrations within a particular window to maximize anti-tumor activity and minimize side effects, especially neutropenia. Many types of tumors are thought to have low but long-term exposure to tumor cells in the body

-16 result in better clinical results. Thus, it would be expected that plasma levels of about 0.03 micromoles could block cell division. Clinical data are available to show that constant intravenous administration over several days to reach a window of approximately 0.05 to 0.1 micromoles in the bloodstream can minimize toxicity and cause tumor regression, sometimes even in patients whose tumors have not responded to 3 -hour infusion modes. The currently proven 3-hour paclitaxel infusion regimens reach peak plasma concentrations that significantly exceed these levels.

The present invention allows paclitaxel to be administered at relatively infrequent daily doses (e.g., approximately twice a day) in accordance with a schedule that would otherwise not be possible or practicable in an intravenous manner. The use of an enhancer (e.g. cyclosporin A) aids the oral absorption of paclitaxel after the first dose and when a second dose of paclitaxel is to be administered later in the day, the use of additional cyclosporin A may not be necessary. Thus, paclitaxel may be administered alternately as a single dose at a set schedule (weekly, biweekly, etc.) or over a period of several consecutive days (e.g., 4 days) every 2 to 4 weeks to target levels safely and efficiently. windows and at reduced toxicity as above.

Another aspect of the present invention relates to a method for selectively enhancing the bioavailability of taxanes and other pharmaceutical compositions. The method comprises orally co-administering to a patient a bioavailability enhancing agent and a formulation comprising a pharmaceutical composition and a solvent. The pharmaceutical composition reaches therapeutic blood levels, but the solvent does not absorb. Because of its physicochemical properties, paclitaxel is typically dissolved in Cremophor for intravenous administration. There has been speculation that Cremophor is responsible for some types of allergic reactions occurring in patients receiving paclitaxel therapy. As a result, patients are restricted to avoid or alleviate hypersensitivity reactions. Paclitaxel should be administered slowly to patients by medical staff, under constant supervision for severe hypersensitivity reactions. For

-17Standard intravenous regimens generally require regimens of H-1 and H-2 blockers plus steroids.

Applicants have found that oral co-administration of a bioavailability enhancer and a taxane formulation comprising taxane, CREMOPHOR® EL and ethanol results in the absorption of taxane, achieving pharmacologically effective or therapeutic blood levels, at negligible levels of Cremophor in the blood could cause adverse side effects. Accordingly, this aspect of the present invention pertains to the use of any solvent-soluble pharmaceutical composition, such as polyalkoxylated castor oil, which tends to cause adverse side effects such as hypersensitivity reactions when administered parenterally. The enhancing agent aids in the uptake or absorption of the pharmaceutical active agent through the intestine, but this effect is not applied with respect to the solvent.

Taxanes are preferred active agents. Other agents include antineoplastic drugs such as chemotherapeutic agents (e.g. etoposide, camptothecin, CPT-11 (Pharmacia / UpJohn), doxorubicin, vincristine, davnorubicin, mitoxanthron, and colchicine), and ganciclovir and foscarnet. In preferred embodiments, certain amounts of the bioavailability enhancing agent and the pharmaceutically active agent are formulated together in a combined oral dosage form. Such dosage forms may include tablets, capsules, capsules, gel tablets, pills, liquid preparations or lozenges. One such combination product comprises from 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 1000 mg / m ² (based on the average body surface area of the patient) and preferably about 50 to 200 mg / m ² , 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 comprises a polyalkoxylated castor oil, such as CREMOPHOR® EL, in an amount of from about 3 mg / ml to about 10 mg / ml.

For pharmaceutical active agents that exhibit antineoplastic activity, co-administration of the enhancer increases activity at sites of highly protected MDR, such as testes and brain. Thus, the present invention enables the treatment of brain tumors such as anaplastic astrocytomas.

In yet other preferred embodiments, the enhancer or combination of enhancers is administered together with the target agent or combination of target agents 10 minutes before, concurrently, and up to two (2) hours after administration of the target agent (s). In this way, a maximum dose of a cyclosporin enhancer can be administered, for example, an amount of about 30 mg / kg patient weight.

The following examples illustrate various aspects of the present invention and demonstrate an unexpected, very substantial increase in oral absorption of paclitaxel. However, these examples are not intended to limit the scope of the present invention in any way or to define specific enhancer or target agents, dose ranges, test procedures or other parameters that would have to be used exclusively in practice of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Six (6) healthy Sprague Dawley rats, all weighing from 225 to 275 grams and aged approximately six to eight weeks, received a single oral dose of paclitaxel at 9 mg / kg. Blood samples were taken from the tail vein of each rat at 0.5, 1, 2, 3, 4 and 6 hours after the paclitaxel dose. Individual samples were centrifuged and serum was separated. Six samples were mixed for each time interval to obtain a simple representative sample. All samples were examined for unchanged paclitaxel using LC / MS with a lower limit of quantitation of 50 pg / ml.

The results of this study are graphically depicted as the bottom curve in Figure 1, which shows that the bioavailability of orally administered paclitaxel in serum was less than 1%.

-19Example 2

Ten (10) healthy Sprague Dawley rats that exhibited the same characteristics as described in the study described in Example 1 were treated with 5 mg / kg oral cyclosporin A followed by an additional 5 mg / kg dose of oral cyclosporin A and 9 mg / kg. kg of oral paclitaxel.

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 paclitaxel administration. After appropriate sample preparation by preparing one composite sample for each group, plasma from each group was evaluated for unchanged paclitaxel.

The results of this study are graphically depicted as the upper curve in Figure 1. It can be seen that paclitaxel plasma levels for this group of animals were several times higher for the first six hours than those for rats of Example 1 receiving paclitaxel alone, these levels at or above. above target therapeutic levels were maintained for (8) eight hours after dosing and these significant plasma levels were maintained over a 24-hour period.

Example 3

A 71-year-old man suffering from prostate cancer for three years agreed to receive an oral dose of paclitaxel and a cyclosporin A enhancer. His body surface area was 2.04 square meters and his body weight was approximately 84 kilograms. After fasting overnight, he received two doses of cyclosporin A (Sandimmune 5 mg / kg) over a one hour period. Immediately after the second dose, the patient drank a dose of paclitaxel Cremophor / alcohol-based solution containing 180 mg dissolved in 120 ml of 5% dextrose in water, ie about 2.0 mg / kg body weight or about 90 mg / m ² body surface area . Standard preconditions that would be administered with a short-term infusion of taxanes were not administered. After drinking the solution, the patient noted that the taste was unpleasant. Within a few hours he had a loose stool. He also experienced hot flashes several hours after dosing, which may have been related to a temporary discontinuation of antihyperesensitive medication. The clinical course was otherwise normal.

Plasma samples were obtained at frequent intervals after paclitaxel administration and evaluated by LC / MS / MS. The results of plasma levels achieved at time intervals are shown in Figure 2. Peaks were reached about 4 hours after dosing and levels of about 0.07 micromoles were reached from about one hour to five hours. Levels comparable to those found in breast cancer patients receiving 96-hour intravenous infusions of paclitaxel (0.05 micromoles) were reported for approximately 10 to 12 hours (Seidman et al., J. Clin. Oncol. 14 1877 (1996).

Example 4 A 75 year old male suffering from prostate cancer for several years received an oral dose of paclitaxel and cyclosporin A. His body surface area was 1.82 square meters and the weight was approximately 72 kilograms. After fasting overnight, he was given cyclosporin A (Sandimmune 5 mg / kg) and oral paclitaxel (180 mg) on the same regimen as in the patient of Example 1, which was approximately 2.5 mg / kg or approximately 100 mg in this patient. / m ² paclitaxel. Again, the standard prediction, as used in short-term infusions of taxanes, was not administered. After drinking the solution, the patient noted that the taste was unpleasant. Within a few hours he had a loose stool. He also experienced a slight decrease in blood pressure after dosing, which may be related to a vasovagal reaction secondary to his fasting and blood withdrawal status. As a precaution, the patient received approximately 100 ml of saline intravenously. After eating lunch, he felt much better and his clinical course was normal.

Plasma samples were obtained at early intervals after paclitaxel administration and evaluated using LC / MS / MS methods. The results of plasma levels achieved at time intervals are shown in Figure 3. Maximum levels were almost 0.3 micromoles and were recorded approximately 4 hours after dosing. Levels greater than 0.07 micromoles were reached from about one hour to ten hours. Again, levels comparable to those found in breast cancer patients receiving 96-hour intravenous infusions of paclitaxel were recorded over approximately 10 to 12 hours.

Figure 4 shows a composite sample of paclitaxel concentration levels 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 cyclosporin, separated by a one hour time span. in accordance with the present invention.

Example 5

Fifty-three (53) human patients with untreatable cancers received oral paclitaxel in combination with CsA as an option, and intravenous (iv) paclitaxel at 175 mg / m ² as a 3-hour infusion as an option. Oral and intravenous formulations of paclitaxel consisted of 6 mg / ml paclitaxel dissolved in a 1: 1 w / w mixture of CREMOPHOR® EL and ethanol. Patients received one of nine dose levels. See Figure 5.) Dose levels 1 and 2 were randomly selected for either oral or intravenous administration. At higher levels (3 to 9), patients received oral paclitaxel during procedure 1 and intravenous paclitaxel during procedure 2.

Prior to oral administration of paclitaxel, patients received oral doses of CsA. Patients received one of 10 dose levels (Figure 5). At dose levels of 2-3, patients received oral CsA solution 10 minutes prior to oral paclitaxel administration. At subsequent doses, CsA was administered in capsules 30 minutes prior to paclitaxel administration. At dose level 4, CsA was administered 10 minutes before and 2 hours after oral administration of paclitaxel.

To prevent hypersensitivity, patients were predicted with dexamethasone, orally 20 mg, 12 and 6 hours prior to intravenous and oral administration of paclitaxel, clemastine, 2 mg, intravenously and cimetidine, 300 mg intravenously, 30 minutes prior to intravenous and oral administration of paclitaxel. Three patients at dose level 8 and all patients at dose level 9 did not receive the above prediction before oral administration of paclitaxel because no CREMOPHOR® EL was detected in the plasma of patients treated with lower doses of paclitaxel. To prevent nausea and vomiting, patients at dose levels 8 and 9 were given granisertron (Kytril ®), 1 mg orally, 1 hour prior to CsA administration.

-22 Paclitaxel levels in urine and plasma were determined using established high performance liquid chromatography (HPLC) procedures. CsA levels were determined from a total blood sample using a fluorescence polarization immunoassay. Ethanol levels were measured from plasma by gas chromatography. CREMOPHOR® EL levels were determined using established HPLC methods.

The area under the concentration-time curve (AUC) was determined using a trapezoidal rule with extrapolation to infinity, using a terminal rate constant K. The terminal half-life (t 1/2) was calculated to be 0.693 / k. Other parameters evaluated were maximum concentration (Cmax), time to maximum concentration (Tmax) and time utilized above the threshold concentrations of 0.05 μΜ and 0.1 μΜ (T> 0.05 μΜ, T> 0.1 μΜ). C max and T max values were determined graphically. T> 0.05 μ> and T> 0.1 μΜ were determined using linear logarithmic interpolation. The reported percentages of administered doses (U _exe r) were calculated as the amount excreted in the urine divided by the actual dose administered, multiplied by 100%. Statistical analyzes of the data were performed using Student's test and Pearson's correlation coefficient. A p value of less than 0.05 was considered statistically significant.

The main types of haematological toxicity following oral administration of paclitaxel were leukocytopenia and granulocytopenia (Figure 6). These toxicities were short-lived and often existed in advance. The non-haematological toxicities following oral administration of paclitaxel as shown in Figures 7A and 7B were nausea, vomiting and arthralgia / myalgia, and generally mild. All serious toxicities were short-lived and uncomplicated. No toxicities usually associated with CsA were observed.

The pharmacokinetic parameters of orally administered paclitaxel are defined in Figure 8. A dose escalation of orally administered paclitaxel from 60 mg / m ² to 120 mg / m ² in combination with CsA, 15 mg / kg, resulted in a significant increase in both AUC and T> 0. , 1 μΜ paclitaxel. Mean AUC values for doses of 60 mg / m ² were 1.65 ± 0.93 μΜ / h and mean T> 0.1 μ 0,1 were 3.7 ± 2.3 h, mean AUC values for doses of 120 mg / m ² were 2 , 55 ± 2.29 μΜ / h and mean T> 0.1 μΜ were 7.9 ± 8.0 h. Further dose increase for orally administered paclitaxel

-23 on average did not result in a further significant increase in AUC or T> 0.1 μΜ of paclitaxel. The CsA dose increase or dose distribution did not result in a further increase in AUC and T> 0.1 μΜ of paclitaxel compared to a single dose of 15 mg / kg. There was great variability between patients at all dose levels.

T

CsA pharmacokinetic parameters are defined in the figure. 9. Dose increase and CsA scheduling resulted in higher AUC values for CsA but Cmax values did not increase. Paclitaxel dose escalation did not provide significant differences in CsA pharmacokinetics. CREMOPHOR® EL plasma levels following oral administration of paclitaxel were undetectable at all paclitaxel dose levels (<0.01% v / v).

The pharmacokinetic data for intravenous paclitaxel were consistent with the results already observed previously.

In summary, CREMOPHOR® EL, which may cause 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, limiting the bioavailability of the drug. No hypersensitivity was observed in patients who did not receive pre-medication to orally administered paclitaxel. Therefore, paclitaxel may be administered orally without detriment to hypersensitivity. In addition, the maximum effect of CsA on increasing paclitaxel exposure was observed at a single CsA dose of 15 mg / kg.

Since various embodiments of the above invention are possible, and since various changes may be made to the above embodiments, it should be understood that all of the facts described herein are to be construed as illustrative only and not to limit the scope of the present invention.

Claims (20)

A method for reducing the incidence or severity of hypersensitivity reactions associated with parenteral administration of a taxane, comprising orally administering to a patient a taxane-containing composition, said composition causing hypersensitivity reactions when administered parenterally. The method of claim 1, wherein said taxane is selected from the group consisting of 2-MPM salts of paclitaxel, docetaxel, taxane, and polymorphs and hydrates thereof. The method of claim 1, wherein said taxane comprises a paclitaxel or docetaxel derivative, analog or precursor. The method of claim 3, wherein said precursor is paclitaxel-2'-MPM or docetaxel-2'-MPM. The method of claim 1, wherein said taxane is paclitaxel or docetaxel. The method of claim 1, wherein said taxane is present in said formulation in an amount of from about 60 to about 250 mg / m ² . 7. A method for selectively enhancing the bioavailability of a pharmaceutical active agent comprising orally co-administering to a patient a bioavailability enhancer and a formulation comprising the pharmaceutical active agent and at least one solvent that achieves an effective blood level when administered parenterally, wherein: said pharmaceutical active agent reaching a therapeutic blood level but said solvent does not reach an effective blood level. The method of claim 7, wherein said solvent comprises polyalkoxylated castor oil. The method of claim 8, wherein said composition further comprises ethanol. -2510. The method of claim 7, wherein said bioavailability enhancing agent is selected from the group consisting of cyclosporins A to Z, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833, and PSC-833. SDE-NIM811. The method of claim 10, wherein said bioavailability enhancing agent is cyclosporin A. The method of claim 7, wherein said bioavailability enhancing agent is orally administered prior to oral administration of said taxane preparation. 13. The method of claim 7, wherein said bioavailability enhancing agent is orally administered after oral administration of said taxane preparation. 14. The method of claim 7, wherein said bioavailability enhancing agent is orally administered substantially concurrently with the oral administration of said taxane preparation. 15. The method of claim 7, wherein said bioavailability enhancing agent is orally administered from about one hour before to about two hours after oral administration of said taxane preparation. 16. The method of claim 7, wherein said pharmaceutically active agent is a taxane. 17. The method of claim 16 wherein said taxane is selected from the group consisting of 2'-MPM salts of paclitaxel, docetaxel, taxane, and polymorphs and hydrates thereof. The method of claim 16, wherein said taxane comprises a derivative, analog or precursor of paclitaxel or docetaxel. The method of claim 18, wherein said precursor is paciitaxel-2'-MPM or docetaxel-2-ΜΡΜ. -2620. The method of claim 16 wherein said taxane is paclitaxel or docetaxel. The method of claim 16, wherein said taxane is present in said formulation in an amount of from about 60 to about 250 mg / m ² . A composition comprising a taxane and a polyalkoxylated castor oil, characterized in that it is in the form of an oral dosage unit.