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/m2was 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.

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Persistent URL dx.doi.org/10.1038/sj.clpt.6100476, hdl.handle.net/1765/29152
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Hooker, A.C., ten Tije, A.J., Carducci, M.A., Weber, J., Garrett-Mayer, E., Gelderblom, H., … Baker, S.D.. (2008). Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: Incorporating cytochrome P450 3A activity measurements. Clinical Pharmacology and Therapeutics, 84(1), 111–118. doi:10.1038/sj.clpt.6100476