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Lack of Association of Single-Nucleotide Polymorphisms in Pregnane X Receptor, Hepatic Nuclear Factor 4, and Constitutive Androstane Receptor with Docetaxel Pharmacokinetics

Authors' Affiliations: ¹ Department of Hematology-Oncology, National University Hospital; ² Department of Biochemistry and ³ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; and ⁴ Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

Requests for reprints: Lai-San Tham, Lilly-NUS Centre for Clinical Pharmacology Pte. Ltd., Level 6, Clinical Research Centre (MD11), National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore. Phone: 65-6413-9913; Fax: 65-6779-0587; Email: Tham_lai_san{at}lilly.com.

Purpose: This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4 (HNF4), on the pharmacokinetics of docetaxel.

Experimental Design: Docetaxel was given as an i.v. infusion of 75 mg/m² over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4 were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model.

Results: Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, 1 acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4 and 5' untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance.

Conclusions: SNPs identified in CYP3A gene expression regulators CAR, HNF4, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.