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Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women

Tanii, Hiromi, Shitara, Yoshihisa and Horie, Toshiharu (2011) Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. European Journal of Clinical Pharmacology, 67 (10). pp. 1017-1025. ISSN 0031-6970


Purpose: Letrozole is an orally active aromatase inhibitor for treatment of breast cancer. The objectives of this study were to examine pharmacokinetic profile of letrozole in Japanese subjects and identify factors which influence variability in PK of letrozole using population pharmacokinetic (PPK) analysis.
Methods: Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.5 mg letrozole once daily for 14 or 28 days. A PPK model was developed using NONMEM software. Age, body weight (WT), AST, ALT, total bilirubin, serum creatinine (CRE), and genotype of CYP2A6 were studied as covariates. Estrone, estrone sulfate, and estradiol in plasma were measured as pharmacodynamic markers.
Results: CYP2A6 genotype, CRE and AST were significant covariates for apparent systemic clearance (CL/F), and WT was a significant covariate for apparent distribution volume (Vd/F). Population mean estimates of CL/F and Vd/F in subjects without CYP2A6 mutation were 1.03 × (CRE/0.70)-1.27 × (AST/17.5)-0.793 L/hr and 94.2 × (WT/51.1)1.12 L, respectively. CL/F in subjects possessing 1 and 2 CYP2A6 mutation alleles were 84.3% and 44.8% of the value in the subjects without mutation, respectively. Estrogen levels fell to below detection limits in most subjects after letrozole administration. Three mild and transient adverse events (upper respiratory tract inflammation, arthralgia, and vomiting) were reported in the study.
Conclusions: CYP2A6 genotype largely influences CL/F of letrozole. Genetic polymorphism of CYP2A6 and body weight will be causes of ethnic difference in PK. However, dose adjustment is not necessary, due to the wide therapeutic range.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: CYP2A6, letrozole, NONMEM, pharmacogenomics, population pharmacokinetic analysis
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15