Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans

Luca Gianni, Christine M. Kearns, Antonio Giani, Giuseppe Capri, Lucia Viganó, Alberta Locatelli, Gianni Bonadonna, Merrill J. Egorin

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. Patients and Methods: Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6α-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. Results: Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6α- hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6α-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6α- hydroxylpaclitaxel, or to paclitaxel peak concentrations (C(max)). Neutropenia was related to the duration that plasma concentrations were ≥ 0.05 μmol/L, a relationship that is well described by a sigmoid maximum response (E(max)) model. Conclusion: The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6α-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are ≥ 0.05 μmol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.

Original languageEnglish
Pages (from-to)180-190
Number of pages11
JournalJournal of Clinical Oncology
Volume13
Issue number1
Publication statusPublished - Jan 1995

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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