Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer
Article first published online: 28 JAN 2010
© 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 69, Issue 5, pages 465–474, May 2010
How to Cite
Koolen, S. L. W., Oostendorp, R. L., Beijnen, J. H., Schellens, J. H. M. and Huitema, A. D. R. (2010), Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer. British Journal of Clinical Pharmacology, 69: 465–474. doi: 10.1111/j.1365-2125.2010.03621.x
- Issue published online: 12 APR 2010
- Article first published online: 28 JAN 2010
- Received 15 June 2009Accepted15 December 2009
- oral administration;
- population pharmacokinetics;
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Docetaxel is an approved drug for the treatment of cancer of various primary origins.
• An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens.
• Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel.
WHAT THIS STUDY ADDS
• This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration.
• Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner.
• The developed model will be used for further development of an oral docetaxel regimen.
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.