Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer
S.L.W. Koolen [1,2], R.L. Oostendorp[1,2], J.H. Beijnen [1,2,3], J.H.M. Schellens [1,2,3], A.D.R. Huitema [1,2]
 Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute / Slotervaart Hospital.  Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute. Division of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Objectives: Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of CYP3A4 by ritonavir (RTV) results in boosted apparent oral bioavailability of more than 100%. The aim of this study was to evaluate the influence of RTV on the absorption, elimination of docetaxel and to assess the influence of the formulation vehicle, polysorbate80, on the disposition of docetaxel.
Methods: Data from two clinical studies (36 patients) were available and consisted of concentration time data of intravenously and orally administered docetaxel with or without co-administration of RTV. Plasma concentrations of both RTV and docetaxel were extensively monitored during the first 48 hours. Population modeling was performed using NONMEM. Starting point of the model development was a well described 3-compartment model for intravenous (iv) docetaxel [1,2]. The iv model was fitted to the data. Secondly, the oral data with or without co-administration of RTV were incorporated into the model. This was performed in a semi-physiological manner. The PK parameters of RTV of each individual were calculated using a previously developed PK model of RTV. RTV was assumed to deactivate the enzyme involved in docetaxel clearance in a reversible and concentration dependent manner. The adequacy of the final model was evaluated with several graphical and numerical methods including a visual predictive check.
Results: Thirty-six patients were included in the two studies, and pharmacokinetic data were assessed from 72 treatment courses. The fraction absorbed increased from 14 to 29% (for RTV co-administration). The inhibition and re-activation of CYP3A4 by RTV occurred instantaneously and was best described by an equilibrium constant (Keq) of 0.12 mL/Ķg. The parameter estimates for the distribution volume of the central compartment differed significantly for iv (9.7L +/- 1L) and orally (74.7L +/- 17.6L) administered docetaxel which is probably caused by the formulation vehicle, polysorbate 80, a strong micelle forming agent. It was investigated whether a time-dependent increase in distribution volume could be identified, however this could not be established.
Conclusions: A pharmacokinetic model was successfully developed that described both the pharmacokinetics of orally and intravenously administered docetaxel in combination with RTV. The relatively small volume of distribution of iv administered docetaxel shows that polysorbate result in a decreased distribution to tissue.
It was shown that the high apparent bioavailability of docetaxel in combination with RTV could mainly be explained by strong inhibition of docetaxel elimination and for a small part by an increased fraction absorbed. The developed model will be used to establish optimal combination regimens and will be extended with PD data.
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