Effect of food on the pharmacokinetic behavior of the potent oral taxane BMS-275183

Purpose: BMS-275183 is a potent oral paclitaxel analogue that previously showed promising activity. The goal of the present trial was to investigate whether food affects the pharmacokinetics of BMS-2751183. Additionally, we evaluated its pharmacokinetic variability using flat-fixed dosing compared with dosing individualized by body surface area (BSA). Patients and Methods: The patients were treated with 200 mg of BMS-275183 under fasting condition (A), after a standard low-fat meal (B), or after a high-fat meal (C). The patients were randomized to one of six treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA). The fourth (D) and consecutive weekly doses were normalized by BSA and consisted of 200 mg/m(2). Pharmacokinetic sampling was done up to 72 hours after the first four doses and analyzed with a validated liquid chromatography/mass spectrometry assay. Results: A total of 31 patients were treated. Pharmacokinetic data were available for 26 patients (A and C), 24 patients (B), and 21 patients (D), Compared with administration under fasted conditions, a decrease of 39% and 63% in the maximal observed drug concentration was observed when BMS-275183 was administered after a low-fat and a high-fat meal, respectively. There was no change in systemic exposure as measured by the area under the plasma concentration versus time curve extrapolated to infinity (AUC(inf)). No apparent relationship was observed between AUC(inf) and BSA for either the 200 mg or the 200 mg/m(2) regimen. BMS-275183 was well tolerated with grade 3 and 4 toxicity in eight patients. One partial response was observed in a non-small cell lung cancer patient. Conclusions: Food intake does not affect the pharmacologic exposure to BMS-275183. BMS-275183 can be given orally by flat dosing instead of BSA-normalized dosing.