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

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and Department of Medical Oncology and Clinical Pharmacology, Tumor Biology Center, and Department of Internal Medicine, University Medical Center, Albert-Ludwigs University Freiburg, Freiburg im Breisgau, Germany.

Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl

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.

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