Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements.
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.
Hooker
A C
AC
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Ten Tije
A J
AJ
Carducci
M A
MA
Weber
J
J
Garrett-Mayer
E
E
Gelderblom
H
H
McGuire
W P
WP
Verweij
J
J
Karlsson
M O
MO
Baker
S D
SD
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*
D043823:Taxoids; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A