Comparative Pharmacokinetics of Unbound Paclitaxel During 1- and 3-Hour Infusions

Abstract

PURPOSE: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent. PATIENTS AND METHODS: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m2 given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion. RESULTS: The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 ± 24.2 v 48.5 ± 24.1 μL·h/mL; P = .002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 ± 0.10 v 0.62 ± 0.12 μmol/L·h; P = .009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P < .005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P = .053), consistent with increased exposure to unbound drug. CONCLUSION: Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.