title: Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements.
abstract: The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.
authors.affiliation: Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: A C
authors.initials: AC
authors.lastname: Hooker
authors.forename: A J
authors.initials: AJ
authors.lastname: Ten Tije
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
authors.forename: J
authors.initials: J
authors.lastname: Weber
authors.forename: E
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.forename: W P
authors.initials: WP
authors.lastname: McGuire
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism* / Q000592:standards*; D000077143:Docetaxel; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008111:Liver Function Tests / Q000592:standards; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D012107:Research Design / Q000592:standards*; D043823:Taxoids / Q000493:pharmacokinetics*
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A