GSK, Collegeville, PA, USA.
GSK, London, UK.
Clin Pharmacokinet. 2024 Sep;63(9):1327-1341. doi: 10.1007/s40262-024-01417-9. Epub 2024 Sep 11.
Daprodustat is a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the USA for treatment of anemia owing to chronic kidney disease (CKD) in dialysis-dependent adults and in Japan for treatment of CKD in dialysis- and non-dialysis dependent adults. This analysis characterized the population pharmacokinetics (PopPK) of daprodustat in adults with CKD and evaluated the influence of intrinsic and extrinsic factors.
This PopPK analysis included data from one phase 2B and four phase 3 studies comprising 707 CKD subjects dose titrated to prespecified target hemoglobin levels with daprodustat doses ranging from 1 to 24 mg once daily and 2 to 48 mg given three times a week (TIW). Model development leveraged a previous phase 1/2 PopPK model. Stepwise covariate analysis included 20 extrinsic and intrinsic factors. Model evaluation used standard goodness-of-fit and visual predictive checks.
Daprodustat PopPK was adequately characterized using a three-compartment distribution model with first-order elimination. The absorption phase was described using five transit compartments. Oral clearance and volume of distribution was 24.6 L/h and 26.9 L, respectively. Body weight dependence (with fixed allometric coefficients) of clearance and volume terms was a statistically significant covariate. Concomitant use of clopidogrel (moderate CYP2C8 inhibitor) decreased oral clearance, resulting in higher area under the plasma concentration-time curve (AUC) ratio of 1.59 (90% CI: 1.39-1.82), subjects' dialysis status (non-dialysis versus dialysis) had an effect on absorption, with C ratio of 1.19 (90% CI: 1.09-1.30). None of the other investigated intrinsic or extrinsic covariates, including concomitant administration with phosphate binders, oral iron and acid reducing agents resulted in a significant change in daprodustat systemic exposure.
The PopPK of daprodustat in the CKD population with anemia was adequately characterized. Allometrically-scaled body weight on clearance and volume, dialysis status on absorption and clopidogrel on clearance were statistically significant covariates.
daprodustat 是一种首创的缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHI），已获美国批准用于治疗透析依赖成人的慢性肾脏病（CKD）相关贫血，以及日本用于治疗透析和非透析依赖成人的 CKD。本分析旨在对 CKD 成人中 daprodustat 的群体药代动力学（PopPK）进行特征描述，并评估内在和外在因素的影响。
本 PopPK 分析纳入了来自 1 项 2B 期和 4 项 3 期研究的数据，这些研究纳入了 707 例 CKD 患者，他们根据预设的目标血红蛋白水平滴定 daprodustat 剂量，剂量范围为 1 至 24 mg 每日 1 次和 2 至 48 mg 每周 3 次（TIW）。模型开发利用了先前的 1/2 期 PopPK 模型。逐步协变量分析纳入了 20 个外在和内在因素。模型评估采用标准的拟合优度和可视化预测检查。
采用具有一级消除的三房室分布模型可充分描述 daprodustat 的 PopPK。吸收阶段采用 5 个转运室描述。口服清除率和分布容积分别为 24.6 L/h 和 26.9 L。体重依赖性（使用固定的全部比例系数）对清除率和容积项有统计学意义的影响。氯吡格雷（中度 CYP2C8 抑制剂）的伴随使用降低了口服清除率，导致 AUC 比值升高至 1.59（90% CI：1.39-1.82），患者的透析状态（非透析与透析）对吸收有影响，C 比值为 1.19（90% CI：1.09-1.30）。未发现其他内在或外在的协变量（包括与磷酸盐结合剂、口服铁剂和酸还原剂的伴随使用）导致 daprodustat 全身暴露有显著变化。
CKD 贫血患者的 daprodustat PopPK 得到了充分的描述。清除率和容积的全部比例体重、吸收的透析状态和清除率的氯吡格雷是有统计学意义的协变量。
