NDLI: From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Koolen, S. L. W. Van Waterschoot, R. A. B. Van Tellingen, O. Schinkel, A. H. Beijnen, J. H. Schellens, J. H. M. Huitema, A. D. R.
Description	Country affiliation: Netherlands Author Affiliation: Koolen SL ( Slotervaart Hospital, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. s.koolen@nki.nl)
Abstract	Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.
File Format	HTM / HTML
ISSN	00912700
Issue Number	3
Volume Number	52
e-ISSN	15524604
Journal	The Journal of Clinical Pharmacology
Language	English
Publisher	Wiley
Publisher Date	2012-03-01
Publisher Place	Great Britain (UK)
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Pharmacology Antineoplastic Agents Administration & Dosage Pharmacokinetics Taxoids Animals Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Genetics Metabolism Drug Evaluation, Preclinical Female Gene Expression Regulation Humans Mice Mice, Knockout Models, Biological P-glycoprotein P-glycoproteins Ritonavir Pharmacology Journal Article
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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