Compositions and methods for administration of pharmacologically active compounds

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A number of preclinical studies and Phase I open-label, dose-ranging clinical studies have been performed to demonstrate the safety, pharmacokinetics and the potential efficacy of ABI-007. The preclinical studies were a combination of in vitro cytotoxicity studies; efficacy studies in mice; acute toxicity studies in mice; acute toxicity studies in rats; studies of myelosuppression in rats; pharmacokinetics studies in rats and an acute toxicity study in dogs.

The in vitro cytotoxicity study in an in vitro tumor model using L1210 murine leukemia cells demonstrated that ABI-007 has equivalent efficacy to TAXOL.

Efficacy was greater for ABI-007 than TAXOL in female athymic Ncr-nu mice implanted with MX-1 mammary tumor fragments. One hundred percent (100%) of ABI-007-treated animals survived after 103 days compared to 20%-40% surviving in groups treated with equivalent doses of TAXOL.

In a series of three pharmacokinetic studies in rats, the pharmacokinetic profile of paclitaxel, formulated as ABI-007, and TAXOL were shown to be similar, but blood/tissue concentration ratios and rates of metabolism varied significantly. ABI-007 is more rapidly distributed out of the blood and is more slowly metabolized. Tissue levels of radio-labeled paclitaxel were higher in several tissues (prostate, spleen, pancreas, and to a lesser extent bone, kidney, lung, and muscle) following administration of ABI-007 when compared to TAXOL. Excretion of paclitaxel following ABI-007 and TAXOL administration was predominantly in the feces.

Toxicity studies have been conducted in mice, rats, and dogs. Single dose acute toxicity studies in mice showed an LD50 dose approximately 59 times greater for ABI-007 than for TAXOL. In a multiple dose toxicity study in mice, the LD50 dose was approximately 10 fold greater for ABI-007 than for TAXOL.

In a 14 day, acute toxicity study in rats, the animals tolerated ABI-007 at doses up to 120 mg/kg, whereas significant morbidity and mortality were reported at doses of 30 mg/kg of TAXOL. Cerebral cortical necrosis was seen in the TAXOL-treated animals. Testicular degeneration was observed in the ABI-007-treated animals.

A single-dose, acute toxicity study was conducted in dogs to determine if the differences observed in the pharmacokinetic profiles of paclitaxel, after doses of ABI-007 and TAXOL resulted in toxicities in a large animal species. The study was conducted using ABI-007, ABI-007 vehicle control, and Human Albumin, USP. TAXOL was not used because of the severe anaphylactic reaction known to be exhibited by dogs due to the Cremophor in the product. With the exception of testicular degeneration in the males (also seen in the rats), the study did not provide useful information. Animals in all groups (active drug and controls) exhibited significant symptoms, which were attributed to an immune reaction to human albumin.

Two further pilot studies were conducted to evaluate the degree of myelosuppression in rats treated with ABI-007 and TAXOL. The results showed that ABI-007 produces considerably less myelosuppression in rats than TAXOL at a dose of 5 mg/kg. The study of the effects of higher doses of ABI-007 (30, 90, 120, 200 mg/kg) showed a dose response relationship in both myelosuppression and decreased body weights with the effect peaking at day 3.

White blood cell counts were back to normal or were elevated by day 14 in surviving animals. Animals in the high dose study showed symptoms of dose-related toxicity.

In a Phase I, intravenous administration, open-label, dose-ranging trial of ABI-007 therapy in patients with advanced solid tumors conducted at M. D. Anderson Cancer Center, more than 80 courses of ABI-007 were administered intravenously over 30 minutes every 3 weeks to 19 patients. The total number of doses of ABI-007 administered was 83. The maximum dose administered was 375 mg/m2, which was administered to six patients (between 25–85 minutes). The maximally tolerated dose was 300 mg/m2, which was also administered to six patients (between 27–60 minutes). The following data for the Phase I study is preliminary, and is representative of all 19 patients; however, data is still outstanding on three patients, who are currently receiving study drug. The 375 mg/m2 dose was associated with dose-limiting toxicities in three out of the six patients. At dose levels of 135 mg/m2 and less than 200 mg/m2, there were no adverse events of myelosuppression or peripheral neuropathy.

ABI-007 was well tolerated at doses up to 300 mg/m2. Most adverse events were Grade 1 or 2 (93%), required no action (83%) and were resolved (78%). No deaths occurred during the study. Five patients had reductions in their study drug dosages, changes in their frequency, interruptions in dosing and/or discontinuation of study drug during the study. All five patients had these changes to their study drug regimen as the result of the development of unacceptable toxicities. Of these five patients, four reported sensory changes, three reported vision-related toxicities, two patients experienced asthenia and two patients experienced thrombocytopenia. All other patients receiving a dose from 135 mg/m2 to 300 mg/m2 showed no such evidence of thrombocytopenia.

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