A semi-mechanistic myelosuppression model of docetaxel treatment in liver impaired patients
Angelica L. Quartino (1), Lena E. Friberg (1), Sharon D. Baker (2) and Mats O. Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
Objectives: Docetaxel is a commonly used anti-cancer drug. Due to higher incidence of severe neutropenia in patients with impaired liver function it is rarely given to these patients. A PK model including covariates have been developed for docetaxel in normal and liver impaired patients [1]. However, it is not yet established if a patient with liver impairment has the same concentration-toxicity relationship as a patient with normal liver function. The aim of the study is to develop a PKPD model describing the docetaxel induced neutropenia in patients with normal and impaired liver function and to explore patient factors that may explain differences in toxicity.
Methods: In the study, 77 cancer patients were treated with docetaxel (75, 50 or 40 mg/m2 depending on liver function). Neutrophils were recorded on day 0, 7, 14 and 21 during one cycle of treatment. Individual concentration-time profiles were generated using the published population pharmacokinetic model for unbound docetaxel [1].
A semi-mechanistic model of myelosuppression [2], with some modification [3], was used to describe the neutrophil time-course, e.g. the drug-related effect was described by a sigmoid Emax model.A step-wise covariate analysis was performed. The covariates evaluated were patient demographics, α1-acid glycoprotein (AAG), haemoglobin and liver function variables: liver function group (LFG) and ERMBT (erythromycin breath test). The patients were divided in to LFG according to their AST, ALT, AP and bilirubin levels, where group 1 has normal liver function and group 2, 3A and 3B has increasing severity of liver impairment [1].
Results: In the first step liver function group was evaluated. Patients with impaired LF (2, 3A, 3B) were found to have a higher baseline (p<0.05) and EC50 (p<0.01) compared to patients with normal liver function. In the second step the remaining covariates were investigated. Patients with high levels of AAG were found to have a lower Emax and a higher Baseline than patients with low AAG levels, which supports earlier findings [4]. The addition of a linear increase in baseline with age further improved the model.
Conclusions: The integrated PKPD model describing the time-course of neutropenia showed that when the difference in PK has been considered, patients with impaired liver function are less sensitive to docetaxel than patients with normal liver function. The model described the data well and showed good simulation properties. Also other factors significantly improved the predictability of the model and decreased the unexplained variability between patients.
References:
[1] Hooker, A et al. Population Pharmacokinetic Model for Docetaxel in Patients with Varying Degrees of Liver Function: Incorporating Cytochrome P450 3A Activity Measurements. Clin Pharmacol Ther. 2008, Jan 8
[2] Friberg, LE et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J. Clin. Oncol. 2002, 20:4713-4721
[3] Quartino, AL et al. An Extended Semi-Physiological Myelosuppression Model following Docetaxel administration with Improved Simulation Properties. ACOP 2008 http://tucson2008.go-acop.org/pdfs/15_quartino.pdf
[4] Kloft, C et al. Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs. Clin Cancer Res 2006 15;12(18):5481-90
