Translational Science Department, Novartis Pharma K.K., 4-17-30, Nishiazabu, Minato-ku, Tokyo 106-8616, Japan.
Eur J Clin Pharmacol. 2011 Oct;67(10):1017-25. doi: 10.1007/s00228-011-1042-3. Epub 2011 Apr 15.
Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis.
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.
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/h 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.
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, because of the wide therapeutic range.
来曲唑是一种用于治疗乳腺癌的口服活性芳香酶抑制剂。本研究的目的是考察来曲唑在日本受试者中的药代动力学特征，并通过群体药代动力学（PPK）分析确定影响来曲唑药代动力学变异性的因素。
25 名健康绝经后日本女性入组本研究，接受 2.5mg 来曲唑每日一次，连续 14 天或 28 天。采用 NONMEM 软件建立 PPK 模型。研究了年龄、体重（WT）、AST、ALT、总胆红素、血清肌酐（CRE）和 CYP2A6 基因型作为协变量。血浆中的雌酮、雌酮硫酸酯和雌二醇被作为药效标志物进行测量。
CYP2A6 基因型、CRE 和 AST 是表观系统清除率（CL/F）的显著协变量，WT 是表观分布容积（Vd/F）的显著协变量。无 CYP2A6 突变受试者的 CL/F 和 Vd/F 的群体平均值估计值分别为 1.03×（CRE/0.70）（-1.27）×（AST/17.5）（-0.793）L/h 和 94.2×（WT/51.1）（1.12）L。携带 1 个和 2 个 CYP2A6 突变等位基因的受试者的 CL/F 分别为无突变受试者的 84.3%和 44.8%。来曲唑给药后，大多数受试者的雌激素水平降至检测限以下。研究中报告了 3 例轻度和短暂的不良事件（上呼吸道炎症、关节痛和呕吐）。
CYP2A6 基因型主要影响来曲唑的 CL/F。CYP2A6 的遗传多态性和体重将是 PK 种族差异的原因。然而，由于治疗窗较宽，不需要进行剂量调整。
