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      Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.

      Clinical cancer research : an official journal of the American Association for Cancer Research
      Adult, Aged, Aged, 80 and over, Albumins, chemistry, Antineoplastic Agents, Phytogenic, adverse effects, pharmacokinetics, therapeutic use, Area Under Curve, Castor Oil, analogs & derivatives, Chemistry, Pharmaceutical, Diarrhea, chemically induced, Dose-Response Relationship, Drug, Female, Humans, Male, Metabolic Clearance Rate, Middle Aged, Nausea, Neoplasms, drug therapy, metabolism, pathology, Nervous System Diseases, Paclitaxel, Particle Size, Stomatitis, Taxoids, Treatment Outcome

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          Abstract

          ABI-007 is a novel Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of Cremophor EL may permit ABI-007 to be administered without the premedications used routinely for the prevention of hypersensitivity reactions. Furthermore, this novel formulation permits a higher paclitaxel concentration in solution and, thus, a decreased infusion volume and time. This Phase I study examines the toxicity profile, maximum tolerated dose (MTD), and pharmacokinetics of ABI-007. ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies. Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel C(max) and area under the curve(inf) values to increase linearly over the ABI-007 dose range of 135-300 mg/m2. C(max) and area under the curve(inf) values for individual patients correlated well with toxicity. ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

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