Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer

Stijn L.W. Koolen, Roos L. Oostendorp, Jos H. Beijnen, Jan H.M. Schellens, Alwin D.R. Huitema

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24 Citations (Scopus)

Abstract

Aim: Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. Methods: Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m-2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. Results: Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 μg ml-1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. Conclusions: A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel.

Original languageEnglish
Pages (from-to)465-474
Number of pages10
JournalBritish Journal of Clinical Pharmacology
Volume69
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Keywords

  • CYP3A4
  • Docetaxel
  • Oral administration
  • Population pharmacokinetics
  • Ritonavir

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