WO2001030448A1 - Methode et compositions pour administration orale de taxanes a des patients humains - Google Patents

Methode et compositions pour administration orale de taxanes a des patients humains Download PDF

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Publication number
WO2001030448A1
WO2001030448A1 PCT/US2000/029633 US0029633W WO0130448A1 WO 2001030448 A1 WO2001030448 A1 WO 2001030448A1 US 0029633 W US0029633 W US 0029633W WO 0130448 A1 WO0130448 A1 WO 0130448A1
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Prior art keywords
taxane
paclitaxel
oral
administered
formulation
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PCT/US2000/029633
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English (en)
Inventor
Samuel Brodor
Kenneth Duchin
Sami Selim
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Baker Norton Pharmaceuticals, Inc.
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Priority to MXPA02004164A priority Critical patent/MXPA02004164A/es
Priority to JP2001532859A priority patent/JP2003512443A/ja
Priority to EP00972373A priority patent/EP1225956A1/fr
Priority to BR0015149-1A priority patent/BR0015149A/pt
Priority to IL14936000A priority patent/IL149360A0/xx
Priority to AU11042/01A priority patent/AU1104201A/en
Priority to HU0203303A priority patent/HUP0203303A3/hu
Priority to SK582-2002A priority patent/SK5822002A3/sk
Priority to CA002389583A priority patent/CA2389583A1/fr
Publication of WO2001030448A1 publication Critical patent/WO2001030448A1/fr
Priority to NO20022008A priority patent/NO20022008L/no

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06Antimalarials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to methods and compositions for orally administering to humans pharmaceutical agents that are poorly absorbed from the gastrointestinal tract, and to methods of treatment of patients through the oral administration of such agents. More particularly, the present invention relates to methods and compositions for orally administering paclitaxel and related taxanes to humans.
  • Paclitaxel is a natural diterpene product isolated from the pacific yew tree (Taxus brevifolia) . It is a member of the taxane family of terpenes . It was first isolated in 1971 by Wani et al . , (J. Am. Chem. Soc . , 93:2325, 1971), who characterized its structure by chemical and X-ray crystallographic methods.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al . , Yale Journal of Biology and Medicine, 64 : 583, 1991; McGuire et al . , Ann. Intern. Med. , 122:273, 1989).
  • CREMOPHOR 1 EL a condensation product of polyethoxylated castor oil and ethylene oxide sold by BASF.
  • NCI National Cancer Institute
  • CREMOPHOR ⁇ EL has proven to be toxic and to produce vasodilation, labored breathing, lethargy, hypotension and death in dogs following IV administration. It is also believed to cause allergic-type or hypersensitivity reactions. Evidence also exists that paclitaxel itself provokes acute hypersensitivity reactions in the absence of CREMOPHOR 8 EL.
  • Paclitaxel analogs derivatized at the 2' and/or 7- positions with groups that enhance water solubility have been synthesized. These efforts have yielded prodrug compounds that are more water soluble than the parent compound and that display the cytotoxic properties upon activation.
  • One important group of such prodrugs includes the 2 ' -onium salts of paclitaxel and docetaxel, particularly the 2'- methylpyridinium mesylate (2'-MPM) salts.
  • Benet et al .
  • This method comprises orally administering such compounds to the patient concurrently with a bioenhancer comprising an inhibitor of a cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein- mediated membrane transport.
  • Benet, et al . provide virtually no means of identifying which bioavailability enhancing agents will improve the availability of specific "target" pharmaceutical compounds, nor does it indicate specific dosage amounts, schedules or regimens for administration of the enhancing or target agents.
  • One aspect of the present invention is directed to a method of reducing incidence or severity of hypersensitivity reactions associated with parenteral administration of a taxane.
  • the method entails orally administering a taxane formulation wherein the formulation causes hypersensitivity reactions when administered parenterally .
  • the taxane is selected from the group of paclitaxel, docetaxel, a derivative, analog, or prodrug of paclitaxel or docetaxel e.g., paclitaxel-2 'MPM and docetaxel-
  • taxane 2 ' MPM salts and polymorphs and hydrates thereof. It is preferred that the taxane is present in the formulation in an amount from about 60 mg/m 2 to about 250 mg/m 2 .
  • Another aspect of the present invention is directed to a method of selectively enhancing the bioavailability of a pharmaceutically active agent.
  • the method involves orally co- administering to a human a bioavailability enhancing agent and a formulation including a pharmaceutically active agent and at least one solvent .
  • Preferred bioavailability enhancing agents include cyclosporins A-Z, dihydrocyclosporin A, dihydrocyclosporin C, acetyl cyclosporin A, PSC-833 and SDZ- NIM 811.
  • the pharmaceutical agent achieves therapeutic blood levels but the solvent that tends to cause the adverse side reactions such as hypersensitivity does not achieve active blood levels.
  • the pharmaceutical agent is a taxane and the solvent is a polyalkoxylated castor oil such as CREMOPHOR ® EL.
  • the CREMOPHOR is present in the formulation in an amount from about 3 to about 10 mg/ l .
  • a further aspect of the present invention is directed to a composition containing a taxane and a polyalkoxylated castor oil (optimally including an excipient) in the form of an oral dosage unit .
  • FIG. 1 is a graph reflecting the circulating levels of paclitaxel in samples taken: (a) lower curve - over a period of 6-8 hours from one group of rats administered only oral paclitaxel, and (b) upper curve - over a period of 24 hours from a second group of rats administered orally one hour prior to the co-administration of oral cyclosporin A and oral paclitaxel .
  • FIG. 2 is a graph reflecting the levels of paclitaxel in plasma samples from a human patient administered oral paclitaxel after two dose of oral cyclosporin A, the first: administered one hour before the paclitaxel dose and the second administered immediately before the paclitaxel.
  • FIG. 3 is a graph reflecting the levels of paclitaxel in plasma samples from a second human patient administered oral paclitaxel by the same regimen as described with respect to FIG. 2.
  • FIG. 4 is a graph reflecting a comparison of the paclitaxel plasma level curves determined over 24 hours in rats (FIG. 1) and in humans (FIGS. 2 ind 3) administered oral paclitaxel after two doses of oral cyclosporin A.
  • FIG. 5 is a table reflecting treatment schedule of oral paclitaxel and cyclosporin used in Example 5.
  • FIG.6 is a table reflecting the hematologic toxicity after oral administration of paclitaxel described in Example c
  • FIGS.7A and 7B are tables reflecting the non- hematologic toxicity after oral administration of paclitaxel described in Example 5.
  • FIG.8 is a table reflecting the pharmacokinetics of oral paclitaxel described in Example 5.
  • FIG.9 is a table reflecting the pharmacokinetics of CsA described in Example 5.
  • FIG. 10 is a graph reflecting the area under the curve (AUC, (uM.h)) of oral paclitaxel versus dose (mg/m 2 ) .
  • a first aspect of the present invention provides a method of preventing or reducing hypersensitivity and allergic reactions in human patients receiving taxane therapy.
  • the method comprises the oral administration of the taxane to the patients. Oral administration by the instantly disclosed method is much less likely than intravenous therapy to produce such adverse reactions.
  • Applicants administered paclitaxel to human patients (see Examples 2 and 3) with no pre-medication (e.g., no H-l H-2 blockers or steroids) .
  • Therapeutic circulating levels of paclitaxel were achieved and no hypersensitivity reactions were observed.
  • taxanes which have been believed to be characterized by therapeutically inadequate oral absorption profiles, can be administered orally to humans with sufficient systemic absorption and oral bioavailability achieved to exhibit plasma levels in the therapeutic range.
  • bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient.
  • Applicants have actually administered the taxane paclitaxel orally to human patients suffering from cancers and have verified that therapeutic blood levels of paclitaxel were achieved in these patients over extended periods of time.
  • the taxane is co- administered with an absorption or bioavailability enhancing agent to a human patient.
  • “Co-administration” of the enhancing agent comprehends administration substantially simultaneously with the taxane (either less than 0.5 hr. before, less than 0.5 hr. after or together), from about 0.5 to about 72 hr. before the administration of the taxane, or both, i.e., with one or more doses of the same or different enhancing agents given at least 0.5 hr . before and one dose given substantially simultaneously with (either together with or immediately before or after) the taxane.
  • "co-administration” comprehends administering more than one dose of taxane within 72 hr. after a dose of enhancing agent, in other words, the enhancing agent (s) need not be administered again before or with every administration of taxane but may be administered intermittently during the course of treatment.
  • the orally administered enhancing agents useful in practicing the preferred embodiment of the invention include, but are not limited to cyclosporins, including cyclosporins A through Z but particularly cyclosporin A (cyclosporin) , cyclosporin F, cyclosporin D, dihydro cyclosporin A, dihydro cyclosporin C, acetyl cyclosporin A, PSC-833, and SDZ-NIM 811 i . e . , ( (Me-lle-4) -cyclosporin, an antiviral, non- immunosuppressive cyclosporin) (both available from Novartis Pharmaceutical Corp) .
  • the structures of cyclosporins A-Z are described in Table 1 below. TABLE 1 Cyclosporins A-Z
  • Cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of about 1200, and that exhibit immunosuppressive properties . They are produced by the members of the genus T ⁇ pycladium, including e . g. , Topycladlum infla tion Gams (formerly designated as Trichoderma polysporum) , Topycladiu terricola and other fungi imperfecti. The major component is cyclosporin A, also referred to as cyclosporine or CsA.
  • CsA cyclosporine
  • several other lesser metabolites, including cyclosporins B through Z have been found to exhibit substantially less immunosuppressive activity than cyclosporin A, or in some cases, no immunosuppressive activity.
  • Cyclosporins are known inhibitors of the P-glycoprotein efflux pump and other transporter pumps as well as of certain cytochrome P450 degradative enzymes, but to date no effective regimens for applying this property clinically have been developed to the point of clinical and commercial feasibility or regulatory approval .
  • a number of synthetic and semi-synthetic analogs have been prepared. See generally Jegorov, et al . , Phytochemistry 38:403-407 (1995).
  • the cyclosporin may be chosen without regard as to whether it exhibits immunosuppressive activity in vivo .
  • One of the surprising discoveries of the invention is that the immunosuppression observed with certain cyclosporins is not inextricably linked to improvement in oral bioavailability of therapeutic agents.
  • cyclosporin F enhances the oral bioavailability of paclitaxel even though it has been reported not to display immunosuppresive activity.
  • paclitaxel which is non-polar and lipophilic, is absorbed. In the absence of this local inhibition, paclitaxel is metabolized to more polar metabolites that do not transverse the mucosa.
  • taxane includes but is not limited to paclitaxel, paclitaxel analogs such as docetaxel (N-debenzoyl- N-tert-butoxycarbonyl-10-deacetyl paclitaxel), derivatives, analogs and prodrugs of paclitaxel and docetaxel e . g. , salts such as paclitaxel-2 ' methylpyridinium (MPM) and docetaxel-2 ' - MPM, taxane 2 ' MPM salts, and polymorphs and hydrates thereof.
  • the dosage range of orally administered taxane target agents will vary from compound to compound based on its therapeutic index, the requirements of the condition being treated, the status of the patient and so forth.
  • the method of the invention makes it possible to administer paclitaxel and other taxanes orally ranging from about 20 mg/m 2 to about 1000 mg/m 2 (based on patient body surface area) or about 2-30 mg/kg (based on patient body weight) as single or divided (2-4) daily doses, and maintain the plasma levels of paclitaxel in humans in the range of 50-500 ng/ml for extended periods of time ⁇ e . g. , 8-12 hours) after each oral dose. These levels are at least comparable to those achieved with 96 -hour IV infusion taxol therapy (which causes the patient great inconvenience, discomfort, loss of quality time, infection potential, etc.) .
  • such plasma levels of paclitaxel are more than sufficient to provide the desired pharmacological activities of the target drug, e . g. , inhibition of tubulin disassembly (which occurs at levels of abut 0.1 ⁇ M, or about 85 ng/ml) and inhibition of protein isoprenylation (which occurs at levels of about 0.03 ⁇ M, or about 25 ng/ml) which are directly related to its antitumor effects by inhibiting oncogene functions and other signal- transducing proteins that play a pivotal role in cell growth regulation.
  • the tumor does not distinguish how the anti- cancer drug was administered.
  • Preferred oral dosage amounts for paclitaxel and other taxanes administered according to the invention are about 60-250mg/m 2 or about 2-6 mg/kg. It may be suitable in some instances to administer to the patient a higher initial loading dose of the target agent to achieve peak blood levels, followed by lower maintenance doses.
  • the dosage range of the enhancing agent co- administered with the taxane in accordance with the invention is about 0.1 to about 20 mg/kg of patient body weight.
  • Two or more different enhancing agents and/or two or more different target agents may be administered together, alternately or intermittently in all of the various aspects of the method of the invention.
  • the present invention may be employed to treat human patients afflicted with cancers, tumors, Kaposi's sarcoma, malignancies, uncontrolled tissue or cellular proliferation secondary to tissue injury, and any other disease conditions responsive to taxanes .
  • carcinoma that may be treated particularly effectively are hepatocellular carcinoma and liver metastases, cancers of the gastrointestinal tract, pancreas, prostate and lung, and Kaposi's sarcoma.
  • non-cancerous disease conditions which may be effectively treated with these active agents administered orally in accordance with the present invention are uncontrolled tissue or cellular proliferation secondary to tissue injury, polycystic kidney disease, inflammatory diseases ⁇ e . g. , arthritis) and malaria, including choroquine- and pyrimethamine-resistant malaria parasites. See, Pouvelle, et al . , J. Clin. Invest. 44:413-417 (1994).
  • the invention is particularly useful in the treatment of patients with primary tumors and metastases.
  • the active ingredient penetrates the gut wall as a result of the co-administration of the cyclosporin enhancer and is taken up by the portal circulation rapidly, 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 IV infusion therapy) . Higher levels of paclitaxel in the liver after oral administration may not be reflected in increased plasma levels because of the high first pass effect of the liver.
  • the method of the invention in selectively producing high blood concentrations of antitumor agents, is particularly valuable in the treatment of liver cancers ⁇ e . g. , hepatocellular carcinoma and liver metastases) , gastrointestinal cancers ⁇ e . g. , colon, rectal) and lung cancers.
  • this aspect of the present invention does not require any particular bioavailability enhancing agent. Nor is it restricted to any specific dosage amounts or regimens. In less preferred embodiments, the taxane is administered without a bioavailability enhancing agent .
  • the dosage unit may be in the form of conventional tablets, capsules (soft gel or hard gel), caplets, gel caps, pills, liquids ⁇ e . g. , solutions, suspensions or elixirs), powders, lozenges, micronized particles or osmotic delivery systems and any other oral dosage forms known in the pharmaceutical arts.
  • the dosage unit is in the form of a liquid and includes paclitaxel or other taxane in a vehicle comprising CREMOPHOR ® EL or other polyalkoxylated castor oil ⁇ e . g.
  • Each dosage unit includes an effective amount of a taxane and a carrier.
  • the carrier may contain one or more of the following ingredients, namely vehicles, fillers, binders or excipients, disintegrants , solvents, sweeteners, coloring agents and any other inert ingredients which are regularly included in pharmaceutical dosage forms for oral administration. See, Remington ' s Pharmaceutical Sciences, 17th edition (1985).
  • paclitaxel or other taxane dosage forms may contain sufficient quantities of the target agent to provide a daily dosage of about 20-1000 mg/m 2 (based on patient body surface area) or about 2-30 mg/kg. mg/kg (based on patient body weight) as single or divided (2-3) daily doses. Preferred dosage amounts are about 50-200 mg/m 2 or about 2-6 mg/kg.
  • Dosing schedules will also vary depending on factors such as the patient ' s characteristics and disease status .
  • Preferred dosing schedules for administration of oral paclitaxel are (a) the daily administration to a patient in need thereof of 1-4 equally divided doses providing about 20- 1000 mg/m 2 (based on body surface area) , and preferably about 50-200 mg/m 2 , with the daily administration being continued for 1-4 consecutive days each 2-3 weeks, or (b) administration for aboit one day each week.
  • the former schedule is comparable to use of a 96 -hour paclitaxel infusion every 2-3 weeks, which is considered by some a preferred IV treatment regimen.
  • Oral administration of taxanes in accordance with the invention actually decreases toxic side effects in many cases as compared with currently utilized IV therapies. Without intending to be bound by theory, Applicants believe that as opposed to IV infusion which produces a sudden and rapid high concentration in blood levels, oral administration results in absorption of the active agent through the gut wall (promoted by the enhancing agents) , a more gradual appearance in the blood levels and a stable, steady-state maintenance of those levels at or close to the ideal range for a long period of time.
  • the plasma levels of the taxanes administered in accordance with preferred embodiments of the present invention are remarkably and surprisingly similar to the levels observed following IV administration.
  • a series of studies with experimental animals showed that steady state plasma levels of paclitaxel were achieved upon oral co-administration with CsA by the third day of the regimen.
  • the levels of the target agent achieved at steady state were comparable to those achieved in patients by a 96-hour IV infusion of paclitaxel.
  • a 27% response rate was found in patients with metastatic breast cancer treated with a continuous 96-hour infusion every three weeks (Siedman et al . , J. Clin Oncol., 24:1877, 1996) who had previously failed 3 -hour infusions of taxane (taxol or taxotene) .
  • Comparable blood level results can be achieved with the treatment methods of the present invention without the discomfort, inconvenience and risks of prolonged IV infusions.
  • FIGS. 1-4 are especially noteworthy in view of the surprising nature of the results.
  • the data reflected in FIG. 1 were generated from studies of paclitaxel administration to rats, but the data reflected in FIGS. 2 and 3 reflect actual concentration levels of paclitaxel over time in the plasma of two human patients administered oral paclitaxel in accordance with the present invention, i.e., with co-administration of an oral cyclosporin enhancing agent .
  • the human data are remarkable not merely because they reflect for the first time, to the extent found in the literature, that paclitaxel was administered orally to human beings requiring paclitaxel therapy, but also because therapeutic-level plasma concentrations were achieved and maintained over about a 10-hour period; indeed, the level of drug seen in the plasma of the human patients were comparable to the levels achieved upon IV administration and the methods used did not bring about serious local or systemic side effects. Furthermore, it should be noted that plasma levels are a reflection of the concentration of paclitaxel in tissue.
  • FIG. 4 reflects a superimposition on the same graph of the plasma concentration curves for paclitaxel over a 24 -hour period following oral co-administration of two doses of enhancer (cyclosporin A) spaced on hour apart with oral paclitaxel administered after the second dose of enhancer (cyclosporin A) spaced one hour apart with oral paclitaxel administered after the second dose of enhancer, said data being derived from the 2 -hour rat study reflected in FIG. 1 and the studies on human patients reflected in FIGS 2 and 3. It may be observed that the three curves on the graph in FIG. 4 (one rat and two human) are of very similar configuration, indicating that the results in human are consistent with the animal test results.
  • the rat is an accepted model for assessing the pharmacokinetics and absorption profiles of chemotherapeutic agents. It is equally well established, however, that results in animals are not predictive of results in humans due to known species-to-species variations. Thus, no clinician or medical practitioner would have administered paclitaxel or other taxanes orally to humans with reasonable confidence based on the animal data alone without any human clinical experience. Furthermore, doctors are unlikely to experiment with drugs in life-threatening conditions, i.e., cancer, when data are unavailable. The present invention, therefore, teaches a method whereby taxanes can be orally administered safely and effectively to humans.
  • the current invention is a vast improvement over the prior art because it allows for the utilization of the beneficial properties of a taxane such as paclitaxel without the necessity of intravenous catheters and time spent in a hospital or chemotherapy clinic, as well as the availability of a clinic and the attendant expense, inconvenience and risk of infection to the patient, pre-medication to avoid hypersensitivity or allergic reactions, and potential adverse effects from the pre-medications themselves.
  • a taxane such as paclitaxel
  • Paclitaxel use is associated with a variety of toxicities and side effects. Two of the most noteworthy toxicities are neutropenia and neuropathy. A variety of clinical data have shown that it would be desirable to keep the circulating plasma concentrations within a certain "window" in order to maximize the anti-tumor activity and minimize the side effects, especially neutropenia. For many tumor types, it is believed that low, but long-term exposure of tumor cells in the body results in better clinical results. Thus, plasma levels of about .03 micromolar would be expected to block cell division.
  • the present invention makes it possible to give paclitaxel in comparatively infrequent daily doses (e.g., about twice/day) according to schedules that would otherwise not be possible or practical with the intravenous route.
  • the use of the enhancer ⁇ e . g. , cyclosporin A) promotes oral absorption of paclitaxel for the first dose and if a second paclitaxel dose is to be given later in the day, the use of additional cyclosporin A may not even be needed.
  • paclitaxel can be given intermittently as single dose on a fixed schedule (weekly, biweekly, etc.) or chronically, over a period of consecutive days (e.g., 4 days) every 2-4 weeks with the goal of keeping the levels within the safe and effective "window” and reducing the toxicities discussed above.
  • Another aspect of the invention is directed to a method of selectively enhancing the bioavailability of a taxane or other pharmaceutical agent.
  • the method entails orally co-administering to a patient a bioavailability enhancing agent and a formulation containing the pharmaceutical agent and a solvent.
  • the pharmaceutical agent achieves therapeutic blood levels but the solvent is not absorbed.
  • Cremophor is responsible for some of the allergic-type reactions experienced by patients receiving paclitaxel therapy.
  • patients are pre-medicated to avoid or reduce hypersensitivity reactions.
  • Paclitaxel must be given slowly to patients, with medical personnel in a state of constant vigilance for severe hypersensitivity reactions.
  • pre-medication regimens of H-l and H-2 blockers plus steroids are generally required.
  • this aspect of the present invention embraces the use of any pharmaceutical agent that is soluble in a solvent such as a polyalkoxylated castor oil that tends to cause adverse side effects such as hypersensitivity reactions when administered parenterally .
  • the enhancing agent facilitates uptake or absorption of the pharmaceutically active agent through the gut but it does not exert this action 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, mitoxanthrone and colchicine) , and ganciclovir and foscarnet .
  • chemotherapeutic agents e.g., etoposide, camptothecin, CPT-11 (Pharmacia/UpJohn)
  • doxorubicin doxorubicin
  • vincristine e.g., davnorubicin
  • mitoxanthrone and colchicine ganciclovir and foscarnet
  • fixed quantities of the bioavailability enhancing agent and the pharmaceutically active agent are formulated together in a combination oral dosage form.
  • Such dosage forms can consist of tablets, capsules, caplets, gel caps, pills, liquids or
  • One such combination product includes from about 0.1 to about 20 mg/kg of one or more of 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 average patient body surface area) , and preferably about 50-200 mg/m 2 , of paclitaxel, docetaxel, other taxanes or paclitaxel or docetaxel derivatives such as paclitaxel 2 ' -MPM or docetaxel 2' -MPM.
  • the solvent contains a polyalkoxylated castor oil such as CREMOPHOR ® EL in an amount of from about 3 mg/ml to about 10 mg/ml .
  • enhancing agent enhances activity at sites highly protected by MDR e . g. , the testes and the brain.
  • the present invention facilitates treatment of brain tumors such as glioblastoma multiforme.
  • the enhancing agent or combination of enhancing agents is co-administered with the target agent or a combination of target agents 10 minutes prior to, concurrent with, and up to two (2) hours after administration of the target agent (s) .
  • the maximum dose of cyclosporin enhancer e.g., an amount of about 30mg/kg of patient body weight, may be administered.
  • 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 treatment of the samples and the creation of one composite sample for the group, the plasma from each sample was assayed for unchanged paclitaxel .
  • Plasma samples were obtained at frequent intervals following the administration of paclitaxel and were assayed by LC/MS/MS. The plasma level results over time are shown in FIG. 2. Peak was reached about 4 hours post dosing and levels above 0.07 micromolar were achieved from about one to five hours . Levels comparable to those found in breast cancer patients receiving 96-hour intravenous infusions of paclitaxel (0.05 micromolar), were present for about 10-12 hours (Seidman et al . , J. Clin. Oncol. 24:1877, 1996).
  • Plasma samples were obtained at frequent intervals following the administration of paclitaxel and were assayed by LC/MS/MS. The plasma level results over time are shown in FIG. 3. The peak level was almost 0.3 micromolar and occurred at 4 hours post dosing. Levels above 0.07 micromolar were achieved from about one to ten hours. Again, levels comparable to those found in breast cancer patients receiving 96 -hour intravenous infusions of paclitaxel, were present for about 12-15 hours.
  • FIG. 4 represents a composite of the paclitaxel concentration levels determined over time in rats (upper curve from FIG. 1) and in humans (curves from FIGS. 2 and 3) following oral administration of paclitaxel and two doses of oral cyclosporin spaced one hour apart, in accordance with the present invention.
  • paclitaxel Fifty-three (53) human patients with incurable malignancies received oral paclitaxel in combination with CsA on one occasion and, intravenous (i.v.) paclitaxel at a dose of 175 mg/m 2 as a 3 -hour infusion on another.
  • the oral and i.v. formulation of paclitaxel consisted of 6mg/ml paclitaxel, dissolved in CREMOPHOR ® EL and ethanol 1:1 w/v. Patients received one of 9 dose levels. (See FIG. 5.) Dose levels 1 and 2 were randomized for either oral and i.v. administration. At all higher levels (3-9), patients received oral paclitaxel during course 1 and i.v. paclitaxel during course 2.
  • CsA Prior to oral paclitaxel administration, patients received oral doses of CsA. Patients received one of 10 dose levels (FIG. 5) . At dose levels 2-3, patients received an oral solution of CsA 10 minutes before receiving oral paclitaxel. At subsequent doses, CsA was administered in capsules 30 minutes before paclitaxel administration. At dose level 4, CsA was administered 10 minutes before and 2 hours after oral paclitaxel administration.
  • Paclitaxel levels in urine and plasma were determined using a validated a high performance liquid chromatography (HPLC) assay.
  • CsA levels were determined from whole blood samples using fluorescence polarization immunoassay.
  • Ethanol levels were measured from plasma using a gas chromatagraph.
  • CREMOPHOR ® EL levels were determined using validated HPLC.
  • the area under the concentration-time curve was estimated by the trapezoidal rule with extrapolation to infinity using the terminal rate constant K.
  • the terminal half-life (tl/2) was calculated as 0.693/k.
  • Other parameters assessed were maximal concentration (Cmax) , the time to maximal concentration (Tmax) and time spent above threshold concentrations of 0.05 ⁇ M and 0. l ⁇ M (T>0.05 ⁇ M, T>0. l ⁇ M) .
  • Cmax and Tmax were determined graphically.
  • T> 0.05 ⁇ M and T> 0. l ⁇ M were determined using linear logarithmic interpolation.
  • the percentage of the administration dose recovered (U exer ) was calculated as the amount excreted in the urine divided by the actual administration dose multiplied by 100%.
  • Statistical analysis of the data was performed using the Student's t-test and the Pearson correlation coefficient. A p value less than 0.05 was regarded as statistically significant.
  • hematological toxicity after oral administration of paclitaxel were leukocytopenia and granuiocytopenia (FIG. 6) . These toxicities were short lasting and often pre-existing.
  • Pharmacokinetic parameters of oral paclitaxel administration are defined in FIG. 8. Dose escalation of oral paclitaxel from 60mg/t ⁇ r to 120mg/m 2 in combination with CsA 15mg/kg resulted in significant increase in both AUC and T>0.1 ⁇ M of paclitaxel. Mean AUC values for the doses 60mg/m 2 : and 120 mg/m 2 were 1.65+/- 0.93 ⁇ M/h and 2.55 +/- 2.29 ⁇ M/h, respectively and mean T>0.1 ⁇ M were 3.7+/- 2.3h and 7.9 +/- 8. Oh, respectively.
  • CsA Pharmacokinetic parameters of CsA are defined in FIG. 9. Dose increment and scheduling of CsA resulted in higher AUC values of CsA but Cmax values were not increased. Dose escalation of paclitaxel did not produce significant differences in pharmacokinetics of CsA. CREMOPHOR ® EL levels in plasma after oral administration of paclitaxel were undetectable at all paclitaxel dose levels ( ⁇ 0.01% v/v) .
  • CREMOPHOR ® EL which can induce hypersensitivity in patients, is not absorbed through the gut when administered orally as a solvent agent for paclitaxel. Additionally, CREMOPHOR ® EL may interfere with the absorption of paclitaxel thereby limiting the bioavailability of this drug. No hypersensitivity was observed in patients who did not receive premedication prior to oral paclitaxel administration. Therefore, paclitaxel can be administered orally without the consequence of hypersensitivity. In addition, the maximum effect of CsA on the enhancement of the exposure to paclitaxel was observed at a single dose of CsA of 15mg/kg.

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Abstract

L'invention concerne des agents antinéoplasiques à base de taxane qui jusqu'alors présentaient une biodisponibilité faible ou inexistante, administrés par voie orale à des patients humains souffrant d'états pathologiques répondant à la taxane, rendus suffisamment biodisponibles pour atteindre des concentrations sanguines à effet thérapeutiques. Dans un mode de réalisation recommandé, la taxane, de préférence du paclitaxel, est co-administrée au patient avec un agent facilitant de cyclosporine, de préférence de cyclosporine A. Un mode de réalisation recommandé consiste à administrer une dose d'agent facilitant oral entre 0,5 et 72 heures environ avant la taxane, et une seconde dose, immédiatement avant, en même temps ou immédiatement après la taxane. L'invention concerne également une méthode de traitement de patients souffrant d'états pathologiques répondant à la taxane, ainsi qu'une méthode d'administration du traitement tout en empêchant ou en réduisant les réactions d'hypersensibilité ou d'allergie sans l'aide de prémédication
PCT/US2000/029633 1999-10-27 2000-10-27 Methode et compositions pour administration orale de taxanes a des patients humains WO2001030448A1 (fr)

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MXPA02004164A MXPA02004164A (es) 1999-10-27 2000-10-27 Metodo y composiciones para administrar taxanos por via oral a pacientes humanos.
JP2001532859A JP2003512443A (ja) 1999-10-27 2000-10-27 タキサンをヒト患者に経口投与するための方法及び組成物
EP00972373A EP1225956A1 (fr) 1999-10-27 2000-10-27 Methode et compositions pour administration orale de taxanes a des patients humains
BR0015149-1A BR0015149A (pt) 1999-10-27 2000-10-27 Método e composições para administração de taxanos oralmente a pacientes humanos
IL14936000A IL149360A0 (en) 1999-10-27 2000-10-27 Method and compositions for administering taxanes orally to human patients
AU11042/01A AU1104201A (en) 1999-10-27 2000-10-27 Method and compositions for administering taxanes orally to human patients
HU0203303A HUP0203303A3 (en) 1999-10-27 2000-10-27 Compositions for administering taxanes orally to human patients
SK582-2002A SK5822002A3 (en) 1999-10-27 2000-10-27 Method and compositions for administering taxanes orally to human patients
CA002389583A CA2389583A1 (fr) 1999-10-27 2000-10-27 Methode et compositions pour administration orale de taxanes a des patients humains
NO20022008A NO20022008L (no) 1999-10-27 2002-04-26 Fremgangsmåte og preparater for oral administrering av taxaner til humane pasienter

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US60/162,310 1999-10-27

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WO2003045357A1 (fr) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Formules pharmaceutiques orales contenant du paclitaxel et des derives, et methodes d'administration de celles-ci
US6750246B1 (en) 2000-02-03 2004-06-15 Bristol-Myers Squibb Company C-4 carbonate taxanes
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
EP1569620A1 (fr) * 2002-10-30 2005-09-07 Spherics, Inc. Agents bioactifs nanoparticulaires
US7345093B2 (en) 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
US7659310B2 (en) 2004-04-27 2010-02-09 Formatech, Inc. Methods of enhancing solubility of agents
US8591942B2 (en) 2009-09-23 2013-11-26 Indu JAVERI Methods for the preparation of liposomes comprising docetaxel
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
EP4059497A1 (fr) * 2021-03-17 2022-09-21 Dompé farmaceutici S.p.a. C5ar1 inhibiteurs pour le traitement des réactions d'hypersensibilité aux taxanes
WO2022195017A1 (fr) * 2021-03-17 2022-09-22 Dompe' Farmaceutici Spa Inhibiteurs de c5ar1 pour le traitement de réactions d'hypersensibilité à des taxanes

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CN101513395B (zh) * 2008-02-20 2011-01-12 单宝华 紫杉醇类双层软胶囊口服制剂药物
JO3737B1 (ar) * 2015-07-21 2021-01-31 Athenex Therapeutics Ltd تركيبات علاجية من باكليتاكسيل تعطى عن طريق الفم ومثبط P-gp لعلاج السرطان

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WO1997015269A2 (fr) * 1995-10-26 1997-05-01 Baker Norton Pharmaceuticals, Inc. Procede, compositions et kits destines a ameliorer la biodisponibilite par voie orale d'agents pharmaceutiques
WO2000078247A1 (fr) * 1995-10-26 2000-12-28 Baker Norton Pharmaceuticals, Inc. Compositions pharmaceutiques orales contenant des taxanes et methodes de traitement dans lesquelles lesdites compositions sont utilisees
WO1997027855A1 (fr) * 1996-01-31 1997-08-07 Bristol-Myers Squibb Company Procede permettant de rendre actifs du point de vue pharmaceutique des taxanes assimilables par voie orale
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WO1999012570A2 (fr) * 1997-09-05 1999-03-18 Glaxo Group Limited Procede, compositions et trousses servant a augmenter la biodisponibilite orale d'agents pharmaceutiques
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6750246B1 (en) 2000-02-03 2004-06-15 Bristol-Myers Squibb Company C-4 carbonate taxanes
US6919370B2 (en) 2000-11-28 2005-07-19 Transform Pharmaceuticals, Inc. Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof
WO2003045357A1 (fr) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Formules pharmaceutiques orales contenant du paclitaxel et des derives, et methodes d'administration de celles-ci
EP1569620A1 (fr) * 2002-10-30 2005-09-07 Spherics, Inc. Agents bioactifs nanoparticulaires
EP1569620A4 (fr) * 2002-10-30 2006-03-22 Spherics Inc Agents bioactifs nanoparticulaires
US7345093B2 (en) 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
US7659310B2 (en) 2004-04-27 2010-02-09 Formatech, Inc. Methods of enhancing solubility of agents
US7687458B2 (en) 2004-04-27 2010-03-30 Formatech, Inc. Pharmaceutical compositions of hydrophobic compounds
US8591942B2 (en) 2009-09-23 2013-11-26 Indu JAVERI Methods for the preparation of liposomes comprising docetaxel
US9402812B2 (en) 2009-09-23 2016-08-02 Indu JAVERI Methods for the preparation of liposomes
US9655846B2 (en) 2009-09-23 2017-05-23 Indu JAVERI Methods for the preparation of liposomes comprising drugs
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US9308195B2 (en) 2012-10-01 2016-04-12 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
US9763880B2 (en) 2012-10-01 2017-09-19 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
EP4059497A1 (fr) * 2021-03-17 2022-09-21 Dompé farmaceutici S.p.a. C5ar1 inhibiteurs pour le traitement des réactions d'hypersensibilité aux taxanes
WO2022195017A1 (fr) * 2021-03-17 2022-09-22 Dompe' Farmaceutici Spa Inhibiteurs de c5ar1 pour le traitement de réactions d'hypersensibilité à des taxanes

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