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Phase 1 and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system (HDDS) for paclitaxel
Abstract
Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic micropar- ticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of adminis- tering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacoki- netics of paclitaxel in this new formulation, and seek evidence of anticancer activity. Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concen- trations were measured by liquid chromatography-tandem mass spectrometry. Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m 2 . Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m 2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Phar- macokinetics of free and total paclitaxel showed biexponential plasma decay and dose propor- tionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas. Conclusions:The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m 2 . The potential of AI-850 as an alternative to other approved paclitaxel
To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.
A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.
The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).
The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.
There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.
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