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From Mouse to Man: Predictions of Human Pharmacokinetics of Orally Administered Docetaxel From Preclinical Studies
Author(s) -
Koolen S. L. W.,
Waterschoot R. A. B.,
Tellingen O.,
Schinkel A. H.,
Beijnen J. H.,
Schellens J. H. M.,
Huitema A. D. R.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010397051
Subject(s) - docetaxel , pharmacokinetics , pharmacology , cyp3a , p glycoprotein , medicine , ritonavir , regimen , oncology , cancer , chemistry , cytochrome p450 , multiple drug resistance , immunology , metabolism , biochemistry , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , antibiotics
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.