Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer.
OBJECTIVE
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 microg 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.
Koolen
Stijn L W
SL
Department of Pharmacy & Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, the Netherlands. s.koolen@nki.nl
Oostendorp
Roos L
RL
Beijnen
Jos H
JH
Schellens
Jan H M
JH
Huitema
Alwin D R
AD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077143:Docetaxel; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D019438:Ritonavir