Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA.
CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):728-738. doi: 10.1002/psp4.12347. Epub 2018 Sep 30.
This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.
本分析描述了非瓣膜性心房颤动 (NVAF) 患者中阿哌沙班的群体药代动力学 (PPK)，并定量评估了内在和外在因素对暴露量的影响。该 PPK 模型是使用 I-III 期研究的数据开发的。阿哌沙班的暴露情况由具有一级吸收和消除的两室 PPK 模型描述。表观清除率的预测协变量包括年龄、性别、亚洲人种、肾功能和伴随的强/中度细胞色素 P450 (CYP)3A4/ P-糖蛋白 (P-gp) 抑制剂。个体协变量的影响通常导致阿哌沙班的暴露量相对于参考 NVAF 受试者（非亚洲人、男性、65 岁、体重 70kg 且无伴随 CYP3A4/P-gp 抑制剂）变化<25%，但严重肾功能不全除外，其暴露量比参考受试者高 55%。剂量减少算法导致中位暴露量降低约 27%，2.5mg 和 5mg 组之间有较大重叠。亚洲人种对阿哌沙班暴露量的影响<15%，且无临床意义。
