title: From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.
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.
authors.affiliation: Slotervaart Hospital, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. s.koolen@nki.nl
authors.forename: S L W
authors.initials: SL
authors.lastname: Koolen
authors.forename: R A B
authors.initials: RA
authors.lastname: van Waterschoot
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D004353:Drug Evaluation, Preclinical; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019438:Ritonavir / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008565:Membrane Proteins
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D019438:Ritonavir; D043823:Taxoids; C095122:multidrug resistance protein 3; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins