Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: Incorporating cytochrome P450 3A activity measurements

A. C. Hooker, A. J. Ten Tije, M. A. Carducci, J. Weber, E. Garrett-Mayer, H. Gelderblom, W. P. McGuire, J. Verweij, M. O. Karlsson, S. D. Baker

Research output: Contribution to journalArticlepeer-review

Abstract

The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m2 was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.

Original languageEnglish (US)
Pages (from-to)111-118
Number of pages8
JournalClinical pharmacology and therapeutics
Volume84
Issue number1
DOIs
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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