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Comparative Study
. 2008 Jul;84(1):111-8.
doi: 10.1038/sj.clpt.6100476. Epub 2008 Jan 9.

Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements

A C Hooker  1 , A J Ten Tije, M A Carducci, J Weber, E Garrett-Mayer, H Gelderblom, W P McGuire, J Verweij, M O Karlsson, S D Baker
Affiliations
Comparative Study

Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements

A C Hooker et al. Clin Pharmacol Ther. 2008 Jul.

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.

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Conflict of interest statement

CONFLICT OF INTEREST

Dr. Carducci is a consultant to and on the speaker’s bureau for Sanofi-Aventis.

Figures

Figure 1
Figure 1
Total (Ctot) and unbound (Cu) docetaxel plasma concentration versus time profiles for patients with liver function abnormalities (left column) and normal liver function (right column).
Figure 2
Figure 2
Goodness of fit plots for patients with liver function abnormalities (lower row) and normal liver function (LF) (upper row). The left column shows the observed concentrations (DV) of both bound and unbound docetaxel plasma concentrations versus concentrations for the typical individual in the population (PRED). The right column shows the observed concentrations versus the individual predictions of concentration (IPRE).
Figure 3
Figure 3
Unexplained variability in unbound docetaxel CL as each covariate was added to the model. Unexplained variability is estimated separately for patients with normal and abnormal liver function tests. Abbreviations: LFG, liver function group; body surface area, BSA, alpha-1 acid glycoprotein, AAG.
Figure 4
Figure 4
Association between the erythromycin breath test variable C20,min, and log-transformed unbound docetaxel, estimated from the final population pharmacokinetic model. The symbol (x), represents patients with normal liver function, and the symbols (□), (○), and (Δ) represent patients with liver function abnormalities in liver function groups 2, 3A, and 3B, respectively. The dashed line is a linear-regression analysis of data in patients with normal liver function (R2 = 0.03547; P = 0.177), and the solid line is from data in patients with liver function abnormalities (R2 = 0.603, P<0.0001).
Figure 5
Figure 5
Cross-valudated model predictions of the individual clearance values (TVCLXV,i) compared to individual clearance values estimated from the full data set (CLi). The model predicts the unbound concentrations well, with a mean absolute error of 36%.
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