MXPA99010850A - Method and compositions for administering taxanes orally to human patients - Google Patents

Abstract

Agentes antineoplásicos de la familia de los taxanos que a la fecha han presentado una biodisponibilidad oral limitada o nula se administran oralmente a pacientes humanos que padecen de enfermedades que responden a los taxanos y dichos taxanos se vuelven suficientemente biodisponibles para lograr niveles sanguíneos terapéuticos. En una modalidad preferida, el taxano, de preferencia paclitaxel, es co-administrado al paciente con un agente de realce, ciclosporina oral, de preferencia ciclosporina A. A través de un método preferido, se administra la dosis del realzador oral de aproximadamente 0.5-72 horas antes de la administración de taxano y una segunda dosis del realzador se administra inmediatamente antes del taxano, junto con el taxano o bien inmediatamente después de la administración del taxano. Se ofrece también un método para el tratamiento de pacientes humanos que padecen de enfermedades que responden al taxano, asícomo un método para ofrecer dicho tratamiento mientras se previene o se reduce la hipersensibilidad y las reacciones alérgicas sin requerir de medicación previa.

Description

METHOD AND COMPOSITIONS FOR ORAL ADMINISTRATION OF TAXANES TO HUMAN PATIENTS BACKGROUND OF THE INVENTION The invention relates to methods and compositions for the oral administration to human patients of pharmaceutically absorbed agents in a limited manner from the gastrointestinal tract, and to methods for the treatment of patients through the oral administration of such agents. A principal aspect of the invention relates to methods and compositions for the oral administration of paclitaxel and taxanes related to human patients. Many valuable pharmacologically active compounds can not be effectively administered orally to human patients due to limited or inconsistent systemic absorption from the gastrointestinal tract. All these pharmaceutical agents are therefore generally administered intravenously, which requires the intervention of a doctor or another health professional, causing considerable discomfort and potential local trauma to the patient and requiring up to the administration in an environment Hospital with surgical access in the case of certain IV infusions. One of the important classes of cytotoxic agents that are not normally bioavailable when administered orally to humans are the taxanes, which include paclitaxel, its derivatives and analogues. Paclitaxel (currently marketed as TAXOL® by the Oncology division of Bristol-Myers Squibb) is a natural diterpene isolated from the Pacific yew tree (Taxus brevifolia). It is a member of the taxane family of terpenes. It was isolated for the first time in 1971 by Wani et al. (J. Am. Chem. Soc., 93: 2325, 1971), who characterized its structure by chemical methods and X-ray crystallography. One mechanism for its activity refers to the ability of paclitaxel to bind with tubulin, so It inhibits 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); Kumar, 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 of America (Mark an et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann, Intern. Med., 111: 273, 1989). It is effective for the chemotherapy of several types of neoplasms including breast (Holmes 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 skin neoplasms (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46), lung cancer and carcinomas of the head and neck (Forastire et al., Sem. Oncol., 20:56, 1990). The compound also has potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750, 1994) and malaria. Paclitaxel is only slightly soluble in water and this has created significant problems in the development of suitable injectable and infusion formulations useful for anticancer chemotherapy. Some formulations of paclitaxel for IV infusion have been developed using CREMOPHOR EL ® (polyethoxylated castor oil) as the drug vehicle due to the insolubility of paclitaxel in water. For example, paclitaxel used in clinical trials under the supervision of the NCI has been formulated in 50% CRMOPHOR EL ® and 50% dehydrated alcohol. However, CREMOPHOR EL ®, when administered intravenously, is itself toxic and produces vasodilation, breathing difficulties, lethargy, hypotension and deaths in dogs. It is also believed that it is at least partially responsible for the allergic-type reactions observed during the administration of paclitaxel, even though there is some evidence that paclitaxel itself can cause acute reactions even in the absence of CREMOPHOR. In an attempt to increase the solubility of paclitaxel and to develop safer clinical formulations, studies focused on the synthesis of paclitaxel analogs where the 2 'position and / or position 7 is derived with groups that can increase water solubility.

These efforts provided prodrug compounds that are more water soluble than the parent compound and that show the cytotoxic properties upon activation. A major group of prodrugs of this type include the 2 '-oxon salts of paclitaxel and docetaxel, particularly the 2' -methylpyridinium (2'-MPM) esylate salts. Paclitaxel is very limitedly absorbed when administered orally (less than 1%); see Eisman et al., Second NCI orkshop on Taxol and Taxus (September 1992); Suffness et al., In Taxol Science and Applications (CRC Press 1995). Eiseman et al., Indicate that paclitaxel has a bioavailability of 0% when administered orally, and Suffness et al. Report that oral administration of paclitaxel does not seem possible since there is no evidence of antitumor activity when orally administered up to 160 mg / kg / day. In addition, no effective method has been developed to allow the effective administration of oral paclitaxel (ie, a method to increase the oral bioavailability of paclitaxel) or of other oral taxanes or paclitaxel analogs such as docetaxel that inhibit antitumor activity. For this reason, paclitaxel has not previously been administered orally to human patients, and certainly not in the course of treatment of diseases that respond to paclitaxel. Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl paclitaxel) has been marketed as TAXOTERE® (Rhone-Poulenc-Rorer S.A.) in a parenteral form for the treatment of breast cancer. To date, there has been no reference in the scientific literature to the oral absorption of docetaxel in animals or patients. It has been speculated that, in some cases, the limited or no bioavailability of the drug such as paclitaxel after oral administration is the result of the activity of a multiple drug transporter, a membrane-bound P-cycloprotein that functions as a chrome pump, and energy-dependent transport or evacuation to decrease the intracellular accumulation of drug by extruding xenobiotics from the cell. This P-glycoprotein has been identified in normal tissues of the endothelium secretory, as, for example, the biliary lining, brush border of the proximal tubule in the kidneys and the luminal surface of the intestine, and vascular endothelial cells that line the blood-brain barrier, placenta and testicles. It is believed that the P-glycoprotein evacuation pump prevents certain pharmaceutical compounds from crossing the mucosal cells of the small intestine and, therefore, prevents their absorption into the systemic circulation. Several known non-cytotoxic pharmacological agents inhibit P-glycoprotein, including cyclosporin A (also known as cyclosporin), verapamil, tamoxifen, quinidine and phenothiazines, among them. Many of these studies were aimed at obtaining a greater accumulation of cytotoxic drugs administered intravenously within the tumor cells. In fact, clinical trials were conducted in order to study the effects of ciclosporin on the pharmacokinetic characteristics and toxicity of paclitaxel (Fisher et al., Proc. Am. Soc. Clin. Oncol., 13: 143, 1994); doxorubicin (Bartlett et al., J. Clin. One. 12: 835-842, 1994); and etoposide (Lum et al., J. Clin. One. 10: 1635-42, 1992), all of which are anticancer agents known to be subject to multiple drug resistance.

(MDR). These trials showed that patients receiving intravenous cyclosporin prior to anticancer drugs or in conjunction with such drugs have higher blood levels of these drugs, possibly through reduced body clearance, and had the expected toxicity at substantially higher dosage levels. minors These findings tend to indicate that the concomitant administration of ciclosporin suppressed the MDR action of P-glycoprotein, allowing larger intracellular accumulations of the therapeutic agents. For a general comment on the pharmacological implications for the clinical use of P-glycoprotein inhibitors see Lum et al., Drug Resist Clin. One. Hemat. 9: 319-336 (1995); Schinkel et al., Eur. J. Cancer; 31A: 1295-1298 (1995). In the aforementioned studies that refer to the use of cyclosporin to increase blood levels of pharmaceutical agents, active antitumor agents and cyclosporin were administered intravenously. No suggestion was made in these publications to the effect that cyclosporin could be administered orally to substantially increase the bioavailability of orally administered anticancer drugs and other pharmaceutical agents that are themselves limitedly absorbed from the intestines without producing side effects. important toxins. In fact, in the aforementioned 1995 review paper, Lum et al., Showed that concomitant IV administration of MDR inhibitors and chemotherapeutic agents subject to MDR increased the levels of toxicity and exhibited an increase in serious side effects for patients. . Schinkel et al. Warned briefly of the fact that MDR-1 and P-glycoprotein are abundant in the mucosal cells of the intestines, and that this may affect the oral bioavailability of P-glycoprotein substrate drugs, but they made no suggestion or implied that oral administration of MDR suppression agents could improve the bioavailability of orally unavailable agents. In addition, as Lum et al., Schinkel et al., Warned that P-glycoprotein inhibitors can dramatically increase toxicity in patients undergoing chemotherapy and should therefore be used with caution. In a previous publication, Schinkel et al showed that the absorption of orally ingested ivermectin was increased in homozygous mice for a MDR1 a gene disorder compared to normal mice, demonstrating that the P-glycoprotein plays a paramount role in terms of the reduction of the bioavailability of this agent (Cell, 77: 491-502, 1994). In addition, this study also showed that the penetration of vinblastine into several tissues was increased in the mutant mice. None of the published studies provided a regimen for implementing effective oral administration to humans of drugs with unsatisfactory bioavailability such as for example paclitaxel, for example, indicate the respective dosage ranges and administration scheme for specific target drugs and enhancement agents. better bioavailability to promote oral absorption of each target drug or class of drugs. Methods presented in the art for increasing intestinal absorption of drugs that have been administered to date only parenterally are generally focused on the use of enhancers of permeation and solubility as promoting agents, or coadministration by intraluminal perfusion in the intestine. either thin or via the intravenous route of P-glycoprotein inhibitors, for example Leu et al., Cancer Chemorther Pharmacol., 35: 432-436, 1995 (perfusion or IV quinidine infusion suppresses the evacuation of etoposide in the lumen of the gastrointestinal tract from the blood). But these methods suffer from numerous disadvantages. Agents that enhance solubility and permeability are often neither practical nor effective for oral administration at the required doses and can intee with the pharmacological activity of the target drug. The parenteral administration of P-glycoprotein inhibitors in therapeutic (or almost therapeutic) doses in humans can cause severe clinical consequences. In the case of quinine, for example, IV administration can cause arrhythmias, peripheral vasodilation, gastrointestinal disorders and the like. More importantly, they do not indicate how to administer antitumor agents orally to humans. In the published PCT application WO 95/20980 (published on August 10, 1995), Benet et al. Present a method to increase the bioavailability of orally administered hydrophobic pharmaceutical compounds. This method comprises the oral administration of compounds of this type to the patient concurrently with a bioreactor comprising an inhibitor of a cytochrome P450 3A enzyme or a P-glycoprotein-mediated membrane transport inhibitor. Benet et al., However, offer virtually no means of identifying which bioavailability-enhancing agents will improve the availability of specific "target" pharmaceutical compounds, nor do they indicate specific dosages, schemes or regimens for the administration of target or enhancing agents. In fact, even - when Benet's application presents a list of dozens of potential enhancers (P450 3A inhibitors) and white drugs (substrates of P450 3A), the only combination of enhancers and white agent supported by experimental evidence in the application is ketoconazole as enhancer and cyclosporine A as a white drug. When describing the general characteristics of compounds that can be used as bioreactors by reducing the transport activity of P-glycoprotein, Benet et al. Indicate that they are hydrophobic compounds that, generally but not necessarily, comprise two coplanar aromatic rings, one group positively charged nitrogen or a carbonyl group - a calase that includes a huge number of compounds, most of which would not be able to offer the desired enhancement activity in the case of specific target agents. In addition, the white agent classes presented by Benet et al., Include the vast majority of pharmaceutical agents that appear in the Physicians' Desk Reference list. These inclusion criteria are of no value to physicians who handle safe, practical and effective methods of oral administration of specific pharmaceutical agents. An additional deficiency of the Benet et al. Presentation is the standard applied to determine if the bioavailability of a drug unsatisfactorily absorbed by oral administration has improved. Benet and colleagues indicate that any agent that inhibits P-glycoprotein that, when present in the intestine at a given concentration, reduces the transmembrane transport of Rhodamine 123 by P-glycoprotein in brush border, membrane vesicle or cells containing P-glycoprotein in 10% or more can be considered as a biorealistic agent in this concentration and can be used in the practice of its invention. But an increase of only 10% of the absorption from the intestine of an agent that is not otherwise absorbable is an inadequate increase to render the agent therapeutically valuable for a given purpose. In fact, in accordance with the guidelines of the Federal Food and Drug Administration, two pharmaceutical formulations containing the same active ingredient, but differing in their levels of bioavailability by -20% / + 25%, are still considered bioequivalent because Most drugs a difference of -20% / + 25% in terms of the concentration of the active ingredient in the blood is not significant from a clinical perspective. Approved Drug Products with Therapeutic Equivalence Evaluations (Dept. of HHS, 14th edition 1994). When the FDA determines that two pharmaceutical formulations are bioequivalent, doctors and pharmacists consider these substances freely substitutable among them. In general, Benet and colleagues do not offer lessons that an expert in the field of medicine and pharmacy could follow to identify appropriate combinations of bioreagent / target drug or to design specific treatment regimens and schemes that could render the agents white therapeutically effective with oral administration to human patients. Benet and colleagues also do not offer instructions as to how paclitaxel and other taxanes can be orally administered to humans with therapeutic efficacy and acceptable toxicity. A) Yes, a safe but effective method is required to increase the systemic availability after oral administration to human patients of drugs currently administered only parenterally because they do not present a sufficient or consistent absorption when administered orally, and this method has not been offered in the prior art. Surprisingly, it has been experimentally discovered and verified that the taxane class of antineoplastic agents, particularly paclitaxel, can be orally administered to humans reaching substantial and therapeutic blood levels, and without exaggerated toxicity or exaggerated adverse effects even without the pre-administration of medications. to avoid adverse reactions. The present invention relates in its main aspect to the oral administration of a taxane or a combination of taxanes to human patients suffering from disease conditions that respond to these agents. A preferred embodiment of the present invention is a method for increasing the oral bioavailability in humans of taxanes, which are unsatisfactorily absorbed or which are not absorbed from the gastrointestinal tract or intestine, by prior administration and / or by simultaneous administration to a human patient orally of an agent or a combination of agents ("enhancers") effective to inhibit cell multi-drug resistance. If prior administration is used, the bioavailability enhancing agent or agents that increase bioavailability should be administered in sufficient quantities and within a sufficiently short period of time prior to the administration of the taxane whose bioavailability should be increased (the white drug "or" white agent ") in such a way that a sufficient level of the enhancing agent remains at the site of absorption at the time of administration of the target agent to effectively suppress the activity of the multiple drug transporting substances, metabolic enzymes and / or other factors that prevent or inhibit the absorption in the intestine of the target agent. A second aspect or embodiment of the present invention relates to a method for treating patients suffering from diseases responsive to taxanes through the oral administration of taxanes previously available only by parenteral administration. Another aspect or modality is a method for preventing or reducing hypersensitivity and allergic reactions in patients receiving a taxane therapy. Figure 1 is a graph that reflects the circulating levels of paclitaxel in samples taken: (a) lower curve - over a period of 6-8 hours from a group of rats that received only oral paclitaxel, and (b) upper curve - in a period of 24 hours from a second group of rats that received orally one hour before the co-administration of oral ciclosporin A and oral paclitaxel.

Figure 2 is a graph that reflects the levels of paclitaxel in plasma samples from a human patient who received oral paclitaxel after two doses of oral cyclosporin A, the first one given one hour before the paclitaxel dose and the second administered immediately before of paclitaxel. Figure 3 is a graph that reflects the levels of paclitaxel in plasma samples from a second human patient who received oral paclitaxel in the same regimen as described in relation to figure 2. Figure 4 is a graph that reflects a comparison between the curves of paclitaxel plasma levels determined over 24 hours in rats (figure 1) and in humans (figure 2 and 3) who received oral paclitaxel after two doses of oral cyclosporin A. The present invention pertains in its main aspect to the oral administration of the taxane class of antineoplastic agents, particularly paclitaxel and its derivatives, analogs and prodrugs, and the semi-synthetic analog of paclitaxel docetaxel (N-debensoyl-N-tert-butoxycarbonyl-10). -deacetyl paclitaxel), to human patients suffering from disease conditions corresponding to taxanes. Preferred embodiments or preferred aspects of the invention include (a) methods for the oral administration of taxanes administered hitherto only parenterally with sufficient bioavailability to achieve therapeutic blood levels; (b) methods for the treatment of human patients suffering from disease conditions responsive to taxanes through the oral administration of taxanes; and (c) methods to prevent or reduce hypersensitivity and allergic reaction in patients receiving a taxane therapy. The term "bioavailability" as used herein refers to the systemic availability (i.e., blood / plasma levels) of a given amount of drug administered to a patient. It has now been discovered that taxanes, which have unsatisfactory oral absorption profiles, can be administered orally to humans with sufficient systemic absorption and sufficient bioavailability to exhibit plasma levels within the therapeutic range. In fact, we have administered the taxane, paclitaxel, orally to human patients suffering from cancers and we have verified that the therapeutic blood levels of paclitaxel are achieved in these patients for long periods of time. We have observed in animal studies that certain agents such as cyclosporin A, when administered orally immediately after and / or before drugs such as paclitaxel, increase the absorption of these latter drugs from the intestine to an unexpected and surprising degree. results in the achievement of therapeutic levels. However, it is not clear if these observed results are due to the suppression of the P-glycoprotein pump. It is emphasized that the present invention is not limited to the use of particular oral bioavailability enhancing agents for co-administration with an oral taxane in order to render the latter bioavailable to human patients. The invention is generally found in the oral administration of taxanes to human patients, and is not limited to any specific enhancers, specific dosage amounts or specific regimens or to the use of particular biological mechanisms or specific pharmaceutical techniques to render the taxanes become available for oral administration to humans. The preferred embodiment of the method of the invention for the oral administration to humans of paclitaxel, its derivatives, analogs and prodrugs, and other taxanes comprises the oral administration of a bioavailability enhancement agent or oral absorption to a human patient simultaneously with the oral administration, prior to said oral administration, either simultaneously or before oral administration in order to increase the amount of absorption of the intact target agent into the bloodstream.

The enhancement agents administered orally to the following can be employed in the practice of the preferred embodiment of the invention include, without limitation,: Cyclosporins, including cyclosporins A through Z but particularly cyclosporin A (cyclosporine), cyclosporin F, cyclosporin D, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833, SDZ-NIM 8111 (both from Sandoz Pharmaceutical Corp). The structures of cyclosporins A-Z are described in Table 1 below. The class of oral therapeutic agents orally administered whose oral absorption is increased by the enhancement agents includes, but is not limited to, the following: Paclitaxel, other taxanes, docetaxel and derivatives, and prodrugs of all of the foregoing, particularly their salts 2'- MPM and other 2'-methylpyridinium salts. 1 SDZ-NIM 811 is (Me-lle-4) -cyclosporin, a non-immunosuppressive antiviral cyclosporin. ) TABLE 1 Cicleisporina Aminoáci Cy- 1 2 3 CyA MeBmt Abu Sar Sar Ala CyB MeBmt CyC MeBmt Thr Sar Val CyD Meb t Sar Sar CyE MeBmt Abu Abu Sar CyF deoxy MeBmt CyG MeBmt Nva Sar Sar CyH MeBmt Abu Sar Val Cyl MeBmt cyk deoxy-MeBmt Val Sar Sar CyM CyL Bmt Abu MeBmt Nva Nva MeBmt CyN Sar Sar Sar CyO MeLeu Nva CyP Bmt Thr Sar Sar cyq MeBmt Abu Abu Sar &H &R MeBmt MeBmt Thr &T MeBmt Sar Sar cyu MeBmt Abu Abu Abu Sar Sar T &V MeBmt cyw Mebmt Thr Sar CyX Mebmt Nva Sar CyY Mebmt Nva Sar CyZ Acid Abu Sar MeAmino octyl Cyclosporine Amino Acids Cy- 4 5 6 CyA MeLeu Val MeLeu Cy MeLeu MeLeu Val MeLeu MeLeu Val MeLeu MeLeu Val MeLeu MeLeu Val MeLeu MeLeu Val MeLeu MeLeu Val MeLeu Val MeLeu CyL MeLeu Val MeLeu CyL MeLeu Val MeLeu CyM MeLeu Val MeLeu CyN MeLeu Val MeLeu CyO MeLeu Val MeLeu CyP MeLeu Val MeLeu cyq Val Val MeLeu CyR MeLeu Val Leu CyS Val Val MeLeu CyT MeLeu Val MeLeu cyu MeLeu Val Leu T &V MeLeu Val MeLeu cyw MeLeu Val MeLeu CYX MeLeu Val MeLeu cyy MeLeu Val Leu CYZ MeLeu Val MeLeu Cyclosporine Amino acids cy- 7 8 9 CyA Ala D-Ala MeLeu CyB Ala D-Ala MeLeu CyC Ala D-Ala MeLeu CyD Ala D-Ala MeLeu CyE Ala D-Ala MeLeu CyF Ala D-Ala MeLeu CyG Ala D-Ala MeLeu CyH Ala D-Ala MeLeu Cyl Ala D-Ala MeLeu CyK Ala D-Ala MeLeu CyL Ala D-Ala MeLeu CyM Ala D-Ala MeLeu CyN Ala D-Ala MeLeu CyO Ala D-Ala MeLeu CyP Ala D-Ala MeLeu CyQ Ala D-Ala MeLeu CyR Ala D-Ala MeLeu CyS Ala D-Ala MeLeu CyT Ala D-Ala MeLeu CyU Ala D-Ala MeLeu CyV Ala D-Ala MeLeu CyW Ala D-Ala MeLeu CyX Ala D-Ala Leu CyY Ala D-Ala MeLeu CyZ Ala D-Ala MeLeu Cyclosporine Amino Acids Cy- 10 11 CyA MeLeu MeVal - CyB MeLeu MeVal CyC MeLeu MeVal CyD MeLeu MeVal - CyE MeLeu Val CyF MeLeu MeVal CyG MeLeu Me-Mev CyH MeLeu MeVal Cyl Leu MeVal - CyK MeLeu MeVal CyL MeLeu MeVal CyM MeLeu MeVal CyN Leu MeVal CyO MeLeu MeVal CyP MeLeu MeVal - CyQ MeLeu MeVal CyR Leu MeVal CyS MeLeu MeVal CyT Leu MeVal cyu MeLeu MeVal T &V MeLeu MeVal cyw MeLeu Val CYX MeLeu MeVal CY MeLeu MeVal CYZ MeLeu MeVal cyclosporins are a group of nonpolar cyclic oligopeptides (some of which have a ~ immunosuppressant activity) produced by the Topycladium genus, including, for example, Topycladium inflatum Gams (formerly designated as Trichoder a polysporum), Topycladium terrapin and other imperfect fungi. The main component, cyclosporin A (cyclosporin or CsA), has been identified together with several other minor metabolites, such as, for example, cyclosporins B to Z, some of which show substantially lower immunosuppressive activity than the immunosuppressive activity of the cyclosporin A. Several synthetic and semi-synthetic analogs were also prepared. See generally Jegorov et al., Phytochemistry, 38: 403-407 (1995). The present invention encompasses natural, semi-synthetic and synthetic analogues of cyclosporins. Cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of approximately 1200. They are used intravenously or orally, as immunosuppressants, primarily for organ transplants and some other conditions. Cyclosporins, particularly cyclosporine (cyclosporin A), are known inhibitors of the P-glycoprotein pump and other transport pumps as well as certain P450 degrading enzymes, but to date no effective regimen has been developed to apply this ownership clinically to the point of achieving clinical or commercial feasibility or approval by regulatory authorities. One of the surprising findings of the invention is that the immunosuppression observed with certain cyclosporins is not inextricably related to the improvement of the oral bioavailability of the therapeutic agents. Thus, cyclosporin F improves the oral bioavailability of paclitaxel even when, according to reports in the literature, it does not present any immunosuppressive activity. Stewart et al., Transplantation Proceedings, 20 (Supp.3) 989-992 (1988); Granelli-Piperno et al., Transplantation, 46: 53S-60S (1988). Another possible explanation for the observed increased bioavailability of paclitaxel is that there may be interaction at the level of the enzymes that metabolize the drug for ciclosporin and paclitaxel. It is known that both agents are highly metabolized by the cytochrome P-450 system (for example P-450 3A) which is concentrated in the liver as well as in the small intestine. It is conceivable that cyclosporin that was administered first may have inhibited these enzymes in such a way that paclitaxel, which is non-polar and lipophilic, could be absorbed. In the absence of this local inhibition, paclitaxel would be metabolized into more polar metabolites that could not pass through mucosal cells. This theoretical inhibition of the intestinal metabolism of the target agent may have little or no effect on the increasing systemic blood levels when the target agent is administered intravenously in addition, since the primary effect of the oral absorption increase agent may be a local effect on the intestinal lumen, subtherapeutic doses (for example in terms of immunosuppression) should be effective to achieve the desired effect. This is an important consideration in the case of enhancing agents such as for example cyclosporins which have potent immunosuppressive activity and which can present toxicity problems if administered at high levels. Our observation in the sense that non-immunosuppressive cyclosporins, such as cyclosporin F, can continue to function as an oral enhancer, is of great clinical value. It is important to note that while we offer hypotheses regarding the mechanisms of action that are at the basis of our invention, we do not really know what the mechanism is or what are the mechanisms responsible for these surprising findings discussed here; and this does not prevent an expert in the field from practicing the described invention. It may be the case that none of the suggested mechanisms, some of them, or all of them play a role in experimentally and clinically verified improvement of the oral bioavailability of taxanes (specifically paclitaxel). The dosage range of the enhancing agent to be co-administered with the target agent according to the present invention is from about 0.1 to about 20 mg / kg of patient's body weight. The "co-administration" of the enhancing agent encompasses substantially simultaneous administration with a target agent (either less than 0.5 hour before, less than 0.5 hour later or together), from about 0.5 to about 72 hours prior to agent administration white, or both, that is, with one or more doses of the same enhancing agent or of different enhancing agents administered at least 0.5 hour before and a dose administered substantially simultaneously with (either jointly or immediately before or after) the white agent. In addition, the term "co-administration" encompasses the administration of more than one dose of target agent within 72 hours after the administration of a dose of enhancing agent, in other words, the enhancing agent or enhancement agents do not have to administered either through before or with each administration of the target agent, but may be administered intermittently during the course of treatment. The dosage range of oral agents administered orally varies according to the compound based on its therapeutic index, the requirements of the condition being treated, the condition of the patient, etc. The method of the invention makes it possible to administer paclitaxel and other taxanes orally within a range of about 20 mg / square meter to about 1000 mg / square meter (based on the surface area of the patient's body) or about 2-30 mg / kg (based on the patient's body weight) as a single or divided daily dose (2-3), and maintain plasma levels of paclitaxel in humans within the range of 50 to 500 ng / ml for extended periods (e.g. , from 8 to 12 hours) after each oral dose. These levels are at least comparable with those achieved with a therapy with taxol in IV infusion of 96 hours (which causes the patient much discomfort, loss of quality of life, potential for infection, etc.). In addition, such plasma levels of paclitaxel are more than sufficient to provide the desired pharmacological activities of the target drug, for example, inhibition of tubulin disassembly (occurring at levels of approximately 0.1M, or approximately 85 ng / ml) and inhibition of protein isoprenylation (occurring at levels of approximately 0.03in (occurring at levels of approximately 0.03μM, or approximately 25 ng / ml) that are directly related to its antitumor effects by inhibiting oncogenic functions and other transduction proteins of signals that play a central role in the regulation of cell growth The preferred oral dosage amounts for paclitaxel and other taxanes administered in accordance with the present invention are from about 50-200 mg / square meter or about 2-6 mg / kg It may be appropriate in some cases to administer a loading dose to the patient highest initial blank agent in order to achieve peak blood levels, followed by lower maintenance doses. Two or more different enhancing agents and / or two or more different white agents can be administered jointly, alternately or intermittently in all aspects of the method of the invention. The present invention also encompasses methods for the treatment of human patients suffering from cancers, Kaposi sarcoma tumors, malignancies, uncontrolled tissue or cell proliferation after a tissue injury, and any other disease that responds to paclitaxel, taxanes, docetaxel, and / or prodrugs and derivatives of all of the foregoing, such as paclitaxel 2'-MPM, and docetaxel 2"-MPM, orally administered dosage forms comprising one or more of these agents, Among the types of carcinoma that can be treated in a particular manner. effective with oral paclitaxel, docetaxel or other oral taxanes, and their prodrugs and derivatives, hepatocellular carcinoma and hepatic metastases, cancers of the gastrointestinal tract, pancreas, prostate and lung, as well as Kaposi's sarcoma are examples of non-cancerous conditions that can be treated effectively with these active agents administered orally in accordance with the present invention are uncontrolled tissue or cell proliferation after a tissue injury, polycystic kidney disease, inflammatory diseases (e.g., arthritis) and malaria, include malaria parasites resistant to chloroquine and pyrimethamine (Pouvelle et al., J Clin. Invest., 44: 413-417, 1994). Antitumor agents that were administered to human patients to date only parenterally can now be administered to humans in accordance with the present invention by way of time with sufficient bioavailability to offer pharmacologically active blood concentrations that will be particularly effective for the treatment of patients with primary tumors and metastases. The active ingredients will penetrate through the intestinal wall as a result of prior and / or concomitant administration of cyclosporin enhancers and will be rapidly absorbed into the portal circulation, providing a higher local initial concentration of the chemotherapeutic agents in the liver (a local concentration higher than that currently achieved with an IV infusion therapy) than in the general systemic circulation or in most other organs at 1 and 7 days. In addition, it should be noted that the highest levels of paclitaxel in the liver after oral administration may not be reflected in increased plasma levels due to the high first-pass effect of the liver. The method of the present invention, by selectively producing high blood concentrations of antitumor agents, is particularly valuable for the treatment of liver cancers (e.g., hepatocellular carcinoma and liver metastases), gastrointestinal cancers (e.g., colon, rectum) and lung cancers. . The plasma levels of the active target agents orally administered with the appropriate enhancing agents according to that indicated in the present invention are remarkably and surprisingly similar to the plasma levels observed with Administration IV. A series of studies with experimental animals showed that paclitaxel steady state plasma levels were reached through oral co-administration with CsA on the third day of the regimen. The levels of the target agent reached at steady state were comparable to those achieved in patients with a 96-hour IV infusion of paclitaxel. A response rate of 27% was found in patients who failed with taxane with metastatic breast cancer treated with a continuous infusion of 96 hours every 3 weeks (Seidman et al., J. Clin. Oncol., 14: 1877, 1996) . It is believed that similar results can be achieved with the methods of treatment of the present invention, without the discomfort and risks related to prolonged IV infusions. The data reflected in figures 1-4 are especially remarkable and surprising. As described in more detail in the examples presented below, the data reflected in Figure 1 were generated from studies of administration of paclitaxel to rats, but the data reflected in figures 2 and 3 show the actual concentration levels of paclitaxel over time in the plasma of two human patients who received oral paclitaxel according to the present invention, ie, with the co-administration of an oral cyclosporin enhancing agent. The human data are remarkable not simply because they reflect for the first time to the extent that it is found in the literature, that paclitaxel was administered orally to humans who required a paclitaxel therapy, but also because the plasma concentrations of therapeutic levels were reached. and maintained about a period of 24 hours; in fact, the drug levels observed in the plasma of human patients were comparable with the levels reached with IV administration and the methods employed did not cause serious systemic or local side effects. Apart from the animal test data (rats) reported in the examples below and shown in Figures 1 and 4, we carried out a wide series of studies in rats where paclitaxel and other taxanes were orally administered together with cyclosporin A and other cyclosporin enhancers of bioavailability C, D, F and G, and the results of these studies were reported and illustrated in the original co-pending application serial number 08 / 733,142. In addition, the effects of the oral administration of taxanes, particularly paclitaxel, on animal subjects concomitantly with oral doses of cyclosporins were compared in the original application with the administration of the same agents alone, by IV and orally, and administration of other potential but less effective bioavailability-enhancing agents together with the target drugs. The presentations and experimental examples of the application serial number 08/733, 142 are incorporated herein by reference. It has now been found that the pharmacokinetic profile in the rat of paclitaxel co-administered with oral cyclosporin A is quite comparable to the profile in human patients receiving the same regimen. In fact, Figure 4 reflects an overlap in the same graph in the plasma concentration curves for paclitaxel in a period of 24 hours after the oral co-administration of two doses of enhancer (cyclosporin A) spaced for a period of one hour with oral paclitaxel administered after the second dose of enhancer, these data are derived from the study with rats of 24 hours presented in figure 1 and the studies on human patients presented in figures 2 and 3. It can be seen that the 3 curves in the graph of figure 4 (one rat and 2 humans) presented a very similar configuration, which indicates that the results in humans confirm the results obtained in animal tests. The current request does not diminish or subtract the importance and relevance of the data obtained with rat. The rat is an accepted model for evaluating the pharmacokinetic characteristics and absorption profiles of chemotherapeutic agents. However, due to known variation from species to species, no physician or medicine specialist would administer paclitaxel or other taxanes orally to humans with confidence based solely on data obtained from animals without any human clinical experience. Contrary to conventional wisdom in the art, we have taught and provided a method by which taxanes can be orally administered safely and effectively to humans. From the perspective of a physician, the present invention is a significant improvement compared to the prior art, and teaches that the pharmacological properties of a taxane such as paclitaxel can be employed in clinical practice without the requirement of intravenous catheters and time spent in a hospital or a chemotherapy clinic, without the associated expenses, inconveniences and risks of infection for the patient, and even without premedication to avoid hypersensitivity or to avoid allergic reactions, and potential adverse effects of the previous medications themselves. Oral dosage forms of target agents whose bioavailability is increased by the coadministration of enhancing agents can take the form of conventional tablets, capsules (hard gel or soft gel), gel capsules, pills, liquids (e.g. solutions, suspensions or elixirs), powders, pills, micronized particles or osmotic administration systems or many other oral administration forms known in the pharmaceutical art. Liquid preparations may include, for example, paclitaxel or other taxanes in a vehicle comprising CREMOPHOR EL or another polyethoxylated castor oil, alcohol and / or a polyoxyethylated sorbitan monooleate (for example TWEEN ® 80, ICI Americas, Inc. ) with or without flavoring. Each dosage form includes an effective amount of a pharmaceutically inert, taxane white agent and ingredient, for example, conventional excipients, vehicles, fillers, binders, disintegrants, solvents, solubilizing agents, sweeteners, coloring agents, and other inactive ingredients regularly. included in pharmaceutical dosage forms for oral administration. Many of these dosage forms and oral vehicles immediately following the list of active ingredients are presented in Remington's Pharmaceutical Sciences, 17th edition (1985). The precise amounts of each of the white drugs in the oral dosage forms vary according to the age, weight, disease, and condition of the patient. For example, the dosage forms of paclitaxel or another taxane may contain sufficient quantities of the target agent in order to provide a daily dosage of about 20-1000 mg / square meter (based on the patient's body surface area) or either approximately 20-30 mg / kg (based on the patient's body weight) as single daily doses or divided daily doses (2-3). Preferred dosage amounts are between about 50 and 200 mg / square meters or about 2-6 mg / kg. Dosage schemes for the method of treatment of the present invention, for example the treatment of paclitaxel-responsive diseases with co-administered oral paclitaxel dosage forms with enhancing agents, can be adjusted in the same manner to take into account characteristics of the patient and the state of the disease. Preferred dosage schedules for the oral administration of paclitaxel are (a) daily administration to a patient that requires such administration of 1-3 equally divided doses that deliver approximately 20-1000 mg / square meter (based on body surface area) ), and preferably approximately 50-200 mg / square meter, said daily administration continues for 1-4 consecutive days every 2-3 weeks or (b) administration approximately 1 day per week. The first scheme is comparable to the use of a 96 hour paclitaxel infusion every 2-3 weeks, which is considered by some experts as a preferred IV treatment regimen.

The oral administration of taxanes according to the present invention can in fact decrease the toxic side effects in many cases in comparison with the IV therapy currently used. Instead of producing a sudden and rapid high concentration of blood levels as is usually the case with an IV infusion, the absorption of the active agent through the intestinal wall (promoted by the enhancers) offers a more gradual appearance at the levels blood and maintenance of a stable state of equilibrium of these levels or close to the ideal range for a long period of time. In accordance with another aspect of the invention, oral combination dosage forms containing fixed amounts of at least one enhancing agent and at least one target agent are provided. For example, such dosage forms may consist of tablets, capsules, gelatin capsules, pills, liquids, lozenges and other conventional oral dosage forms containing an effective oral bioavailability enhancer amount of an anti-tumor or anti-tumor agent as active ingredients. -neoplastic, as well as suitable inactive ingredient. A combination product of this type includes from about 0.1 about 20 mg / kg of one or more of the cyclosporins A, B, C, F and G, dihydro CsA, dihydro CsC and acetyl CsA together with from about 20 to about 1000 mg / square meter (based on average patient's body surface area), and preferably approximately 50-200 / square meter, of paclitaxel, docetaxel, other taxanes or either paclitaxel or docetaxel derivatives such as paclitaxel 2 '- MPM or docetaxel 2 '-MPM. The co-administration of enhancement agents with the white drugs promotes not only the oral bioavailability of these agents but also allows their use in the treatment of tumors in sites highly protected by MDR, such as, for example, the testes and the brain. Another aspect of the present invention is therefore a method for delivering antitumor drugs to tumor sites protected by MDR through oral co-administration of anti-tumor agent enhancement agents, making it possible to treat brain tumors such as glioblastoma multiforme. Additional advantages of the present invention are found in the area of security. Due to its physicochemical properties, paclitaxel must be solubilized in a mixture of Cremophor / ethanol and this vehicle may be responsible for at least some of the allergic-type reactions experienced by patients treated with paclitaxel. Other solubilizing agents have been employed but none have been as suitable as Cremophor / ethanol. Paclitaxel should be administered slowly to patients, with medical personnel in a state of constant vigilance due to possible severe hypersensitivity reactions. For standard intravenous regimens, pre-medication regimens are generally required with H1 and H2 blockers plus steroids. However, if solubilization with cremophor / ethanol is not used, intravenous taxanes can cause severe reactions after intravenous use. Thus, the administration of docetaxel is related to anasarca and other reactions. Clinically it would be very valuable to have therapies with the potential to eliminate or diminish the need for prior medication in these contexts. The present invention, in one of its modalities, offers a method to prevent or reduce hypersensitivity and allergic reactions in human patients receiving taxane therapy. The method comprises the oral administration of the taxane to patients. It is much less likely that oral administration according to the method of the present invention causes adverse reactions of this type than intravenous therapy. In fact, we have administered paclitaxel to a human patient (see examples 2 and 3) without prior medication (ie, with H-1 or H-2 blockers or steroids), and no hypersensitivity reactions were observed while achieving circulating therapeutic levels. In addition, the use of paclitaxel is associated with several toxicities and side effects. Two of these most notable toxicities are neutropenia and neuropathy. Several clinical data have shown that it would be desirable to maintain circulating plasma concentrations within a certain "window" in order to optimize antitumor activity and minimize side effects, especially neutropenia. In the case of many types of tumors, it is believed that a low but long-term exposure of the tumor cells in the body results in better clinical results. Thus, plasma levels of approximately .03 micromolar would inhibit protein isoprenylation of cancer cells and levels of approximately 0.1 micromolar and block the disassembly of microtubules. There are clinical data that show that intravenous administration is observed over several days to achieve a "window" of approximately .05 to .01 micromolar in the circulation can minimize toxicities and cause tumor regressions, sometimes even in patients whose tumors did not correspond to treatment regimens. 3-hour infusion Currently approved 3-hour infusion regimens of paclitaxel reach peak plasma concentrations that greatly exceed these levels. The present invention also makes it possible to administer paclitaxel in relatively infrequent daily doses (for example about 2 times a day) and in accordance with schemes that would not otherwise be possible or practical with the intravenous route. The use of the enhancer (eg cyclosporin A) promotes the oral absorption of paclitaxel for the first dose and if a second dose of paclitaxel is to be administered later in the day, the use of additional cyclosporin A may not even be required. Thus, paclitaxel could be administered intermittently as a single dose in a fixed schedule (weekly, biweekly, etc.) or chronically, over a period of several consecutive days (for example 4 days) every 2-4 weeks in order to maintain the levels within a safe and effective "window". The following examples illustrate various aspects of the invention and demonstrate the unexpected but very important increases in the oral absorption of paclitaxel. These examples are not intended, however, to limit the invention in any way or to present specific enhancers or targets, nor ranges or dosages test procedure or parameters that should be used exclusively to practice the invention. EXAMPLE 1 Six (6) healthy Sprague Dawley rats, weighing between 225 and 275 grams and approximately 6 to 8 weeks of age received a single oral dose of paclitaxel at 9 mg / kg. Blood samples were collected from the tail vein of each rat 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 quantitation of 50 pg / ml. The results of the study are illustrated graphically in the lower curve of Figure 1 which indicates that the bioavailability of paclitaxel administered orally in the serum was less than 1%. EXAMPLE 2 Ten (10) healthy Sprague Dawley rats with the same characteristics as those used in the study described in example 1 were treated with 5 mg / kg of oral cyclosporin A followed one hour after another dose of 5 mg / kg of ciclosporin A oral and 9 mg / kg of oral paclitaxel. Blood samples were collected from the vein of the tail of each rat 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after the administration of paclitaxel. After appropriate treatment of the samples and after the creation of a composite sample for the group, the plasma was assayed for each sample to determine the level of paclitaxel without change. The results of this study are illustrated graphically in the upper curve of the figural. It can be observed that the paclitaxel plasma levels in this group of animals were several times higher during the first 6 hours than in the rats of example 1 that received paclitaxel alone, than the levels at the therapeutic levels "white" or above. these levels were maintained for (8) eight hours after administration and that important plasma levels were maintained during the 24-hour period. EXAMPLE 3 A 71-year-old man with prostate cancer for 3 years gave his consent to receive an oral dose of paclitaxel and an enhancer in the form of cyclosporin A. His body surface area was 2.04 square meters and his weight was approximately 84 kilograms. After fasting during the night, he received two oral doses of cyclosporin A (Sandi mune 5 mg / kg) at an interval of one hour. Just after the second dose, the patient drank a dose of a cremophor / alcohol-based solution of paclitaxel containing 180 mg dissolved in 120 ml of 5% dextrose in water, i.e. about 2.0 mg / kg of body weight or well approximately 90 mg / square meter of body area. No standard prior medications were administered, as would be used in the case of short-term infusions of taxanes.

After drinking the solution, the patient observed that the taste was unpleasant. He presented loose stools for a few hours. He also reported blushing several hours after the administration, which may be related to the temporary suspension of his hypertensive treatment. Their clinical evolution was without notable events outside of these. Plasma samples were obtained at frequent intervals after administration of paclitaxel and said samples were assayed by LC / MS / MS. The results of plasma levels over time are shown in Figure 2. A peak was reached approximately four hours after administration and levels above 0.7 micromolar were reached from about 1 to 5 hours. Levels comparable to those found in patients with breast cancer receiving intravenous infusions of 96 hours of paclitaxel (0.05 micromolar) were observed for approximately 10-12 hours (Seidman et al., J. Clin. Oncol, 14: 1877, 1996). EXAMPLE 4 An elderly patient of 75 years of age with prostate cancer for several 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 kilograms. After fasting during the night, he received the same regimen of cyclosporin A (Sandimmune 5 mg / kg) and oral paclitaxel (180 mg) as the patient in example 1, which was equal to approximately 2.5 mg / kg or approximately 100 mg / square meter of paclitaxel in this patient. Again, no standard pre-medication was administered, as would be used in the case of short-term infusions of taxanes. After drinking the solution, the patient observed that the taste was unpleasant. He presented loose stools for a few hours. He also presented a slight decrease in blood pressure after the administration, which may have been related to a vasovagal reaction secondary to his state of help and blood collection. As a precaution, the patient received approximately 100 ml of an IV saline solution. After eating, he felt much better and the rest of his clinical evolution was without notable events. Plasma samples were obtained at frequent intervals after administration of paclitaxel which were assayed by LC / MS / MS. The results of the plasma levels with the passage of time appear in figure 3. The peak level was 0.3 micromolar and occurred four hours after the administration. Levels greater than 0.07 micromolar were obtained from approximately 1 to 10 hours. Levels comparable to those found in patients with breast cancer receiving intravenous infusions of 96 hours of paclitaxel were observed for approximately 12-15 hours. As previously observed, Figure 4 represents a compound of the concentration levels of paclitaxel determined over time in rats (upper curve of Figure 1) and in humans (curves of Figures 2 and 3) that received oral paclitaxel after two doses of oral cyclosporine at the interval of 1 hour, according to the present invention. It will be noted that the concentration levels achieved in humans do not merely confirm the efficacy of the present invention in making the paclitaxel orally bioavailable for the first time, but that they exceed the concentration levels achieved in the rat model. These results are unexpected and surprising and, until we demonstrated the clinical efficacy of the method of the present invention in humans, it could not have been predicted based on any of the prior art disclosures regarding cyclosporins or other agents and potential enhancements. or in relation to paclitaxel, its derivatives, analogs and prodrugs or other taxanes. Accordingly, it has been shown that methods are provided which achieve the various objects of the invention and which are well adapted to meet the conditions of practical use. Since several possible embodiments of the invention described above can be made, and since several changes can be made in relation to the embodiments presented above, it will be understood that all the subject matter described herein should be interpreted as illustrative and not in a limiting sense. What we claim as novel and that we wish to protect through a patent is presented in the following claims.

Claims (44)

1. CLAIMS 1. The oral administration of a taxane to a human patient suffering from a disease responsive to taxanes, said taxane is administered in an effective amount to treat said disease.
2. 2. The oral administration of paclitaxel to a human patient suffering from a disease responding to paclitaxel, said paclitaxel is administered in an effective amount to treat said disease.
3. 3. Oral administration of docetaxel to a human patient suffering from a disease responsive to docetaxel, said docetaxel being administered in an effective amount to treat said disease.
4. 4. The oral administration to a human patient of a derivative, analog or prodrug of paclitaxel or docetaxel for the purpose of treating the disease responsive to said analogous derivative, or prodrug, the analogous or prodrug derivative is administered in a effective amount to treat said condition.
5. 5. The oral administration of a prodrug of paclitaxel or docetaxel according to claim 4, wherein the prodrug is paclitaxel -2'-MPM or docetaxel-2'-MPM.
6. 6. The oral administration according to claim 2, wherein said effective amount of paclitaxel is from about 2 to 30 mg / kg based on the patient's body weight.
7. The oral administration according to claim 6, wherein said effective amount is about 2-6 mg / kg.
8. The oral administration according to claim 2, wherein said effective amount of paclitaxel is from about 20 to 1000 mg / square meter based on the patient's body surface area.
9. The oral administration according to claim 8, wherein said effective amount is from about 50 to 200 mg / square meter.
10. A method for rendering an orally administrated taxane bioavailable to human patients at a level sufficient to treat diseases responsive to taxanes, said method comprising the oral co-administration of taxane to the patient of an effective amount to treat the disease together with a effective amount of a selected oral bioavailability enhancing agent within the group consisting of cyclosporin A to Z, (ME-lle-4) -cyclosporin, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A.
11. A method according to claim 10 , where said taxane is paclitaxel.
12. 12. A method according to claim 10, wherein said taxane is docetaxel.
13. 13. A method according to claim 10, wherein said taxane is a derivative, analog, or prodrug of paclitaxel or docetaxel.
14. 14. A method according to claim 13, wherein said taxane is the prodrug paclitaxel-2'-MPM or the prodrug docetaxel-2'-MPM.
15. 15. A method according to claim 10, wherein said bioavailability enhancing agent is selected from the group consisting of cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin F, dihydrocyclosporin A, dihydrocyclosporin C, and acetylcyclosporin A.
16. 16. A method according to claim 15, wherein about 0.1 to about 20 mg / kg of the enhancing agent is administered, based on the patient's body weight.
17. 17. A method according to claim 16, wherein about 5 mg / kg of the enhancing agent is administered.
18. 18. A method according to claim 11, wherein said effective amount of paclitaxel is from about 2 to 30 mg / kg based on the patient's body weight.
19. 19. A method according to claim 18, wherein said effective amount is from about 2 to 6 mg / kg.
20. 20. A method according to claim 11, wherein said effective amount of paclitaxel is from about 20 to 1000 mg / square meter based on the patient's body surface area.
21. 21. A method according to claim 20, wherein said effective amount is from about 50 to 200 mg / square meter.
22. 22. A method according to claim 10, where approximately 2 to 30 mg / kg or approximately 20 to 1000 mg / square meter of paclitaxel are co-administered to the patient together with approximately 0.1-20 mg / kg of cyclosporin A.
23. 23. A method in accordance with claim 10, wherein the enhancing agent is administered either a) about 0.5-72 hours before, b) less than 0.5 hour before, together with less than 0.5 hour later, or c) both about 0.5-72 hours before, and another less than 0.5 hour before, together with or less than 0.5 hour after, administration of the taxane.
24. 24. A method according to claim 23, wherein the taxane is paclitaxel and the enhancing agent is cyclosporin A.
25. A method according to claim 10, wherein the taxane and the enhancing agent are each administered in separate oral dosage forms.
26. A method according to claim 10, wherein the taxane and enhancing agent are co-administered in an oral combination dosage form.
27. A method for the treatment of a human patient suffering from a disease responsive to taxanes, said method comprising the oral administration to a patient of an amount of effective taxane to treat the disease.
28. A method according to claim 27, wherein said taxane is paclitaxel.
29. A method according to claim 27, wherein said taxane is docetaxel.
30. A method according to claim 27, wherein said taxane is a derivative, analog or prodrug of paclitaxel or docetaxel.
31. A method according to claim 30, wherein said taxane is a prodrug selected from the group consisting of paclitacel-2'-MPM or docetaxel-2'-MPM.
32. A method according to claim 28, wherein said effective amount of paclitaxel is from about 2 to 30 mg / kg based on the patient's body weight.
33. A method according to claim 32, wherein said effective amount is from about 2 to 6 mg / kg.
34. A method according to claim 28, wherein said effective amount of paclitaxel is from about 20 to 1000 mg / square meter based on the surface area of the patient's body.
35. A method according to claim 34, wherein said effective amount is from about 50 to 200 mg / square meter.
36. A method according to claim 27, wherein said taxane is co-administered to the patient together with an effective amount of a selected oral bioavailability enhancing agent within the group consisting of cyclosporins A to Z, (Me-lle-4) -cyclosporin, dihydrocyclosporin A, dihydrocyclosporin C and acetylcyclosporin A.
37. The method according to claim 36, wherein said bioavailability enhancing agent is selected from the group consisting of cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin F, dihydrocyclosporin C and acetylcyclosporin A.
38. A method according to claim 37, wherein from about 0.001 to about 20 mg / kg of the enhancing agent is administered.
39. 39. A method according to claim 38, wherein about 5 mg / kg of the enhancing agent is administered.
40. 40. A method according to claim 27, wherein approximately 2-30 mg / kg or approximately 20-1000 mg / square meter of paclitaxel are coadministered to the patient together with approximately 0.1-20 mg / kg of cyclosporin A.
41. 41. A method according to claim 27, wherein the enhancing agent is administered either a) about 0.5-72 hours before b) less than 0.5 hour before, together, or less than 0.5 hours later, or c) both about 0.5 -72 hours before and again less than 0.5 hour before, together, or less than 0.5 hour after, administration of the taxane.
42. 42. A method according to claim 41, wherein the taxane is paclitaxel and the enhancing agent is cyclosporin A.
43. 43. A method according to claim 27, wherein the taxane and enhancing agent are each administered in dosage forms. orally separated.
44. 44. A method according to claim 27, wherein the taxane and enhancing agent are administered together in an oral combination dosage form. A method according to claims 10, 11, 27 or 28, wherein said disease is selected from the group consisting of cancers, tumors, malignancies, uncontrolled proliferation of tissues or cells secondary to tissue injury, polycystic kidney disease and malaria . A method according to claim 45, wherein said disease is a cancer selected from the group consisting of hepatocellular carcinoma., metastasis, cancers of the gastrointestinal tract, pancreas, prostate and lung, as well as Kaposi's sarcoma. A method for preventing or reducing hypersensitivity and allergic reactions in human patients receiving a taxane therapy for the treatment of taxane-responsive diseases, said method comprises the oral administration of the taxane to the patient. A method according to claim 47, wherein said taxane is paclitaxel. A method according to claim 47, wherein said taxane is docetaxel. A method according to claim 47, wherein said taxane is a derivative, analog or prodrug of paclitaxel or docetaxel. A method according to claim 50, wherein said taxane is the prodrug paclitaxel-2'-MPM or the prodrug docepaxel-2'-MPM. A method according to claim 47, wherein said taxane is administered to the patient without prior administration of medication to prevent hypersensitivity or allergic reactions to the taxane. A method according to claim 47, wherein the taxane is orally co-administered together with an effective amount of a selected oral bioavailability enhancing agent within the group consisting of cyclosporins A to Z, (Me-lle-4) - cyclosporin, dihydrocyclosporin A, dihydrocyclosporin C and acetylcyclosporin A. A method according to claim 53, wherein said bioavailability enhancing agent is selected from the group consisting of cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin F, dihydrocyclosporin A, dihydrocyclosporin C, and acetylcyclosporin A. A method according to claim 54, wherein said bioavailability enhancing agent is cyclosporin A.