Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
BMC Pharmacol Toxicol. 2024 Aug 26;25(1):57. doi: 10.1186/s40360-024-00783-1.
Febuxostat is commonly used in clinic for the treatment of hyperuricemia. Multiple-peak phenomenon has been observed in human plasma concentration-time profiles of febuxostat, but has not been paid enough attention in previous research. This study takes a pivotal step forward by conducting a comprehensive population pharmacokinetic (PopPK) analysis of febuxostat in a healthy Chinese cohort, with a central focus on delineating its absorption profile under contrasting fasting and fed conditions, while concurrently assessing the influence of food alongside other potential covariates on febuxostat's PK profile. The plasma concentration data used for modeling was obtained from two bioequivalence (BE) studies. Subjects were administered febuxostat 20 mg or 80 mg under fasting or fed condition. Goodness-of-fit plots, visual predict check (VPC), and normalized prediction distribution error (NPDE) were used for model evaluation. Based on the established model, PK profiles in healthy Caucasian subjects were simulated with parameter adjustment for race difference on clearance and bioavailability. Data from 128 subjects were used in the PopPK analysis. Febuxostat concentration-time curves were described by a two-compartment model with two deposit absorption compartments and lag times (Tlag). Prandial states (Food) showed significant impact on absorption rate ka1 and ka2, as well as Tlag1, and body weight was identified as a significant covariate on the apparent distribution volume. The PopPK analysis of febuxostat in healthy Chinese volunteers, under both fasted and fed conditions, successfully characterized its PK profile and underscored the significant influence of food on absorption. The potential difference of absorption between Chinese population and Caucasian population indicated from the simulations needs further investigation.
非布司他常用于临床治疗高尿酸血症。在人体血浆浓度-时间曲线中观察到非布司他存在双峰现象，但在以前的研究中没有得到足够的重视。本研究通过对健康中国队列中的非布司他进行全面的群体药代动力学（PopPK）分析，向前迈出了重要的一步，重点描述了在禁食和进食两种条件下的吸收曲线，并同时评估了食物以及其他潜在协变量对非布司他 PK 曲线的影响。用于建模的血浆浓度数据来自两项生物等效性（BE）研究。受试者在禁食或进食条件下分别接受 20mg 或 80mg 的非布司他治疗。采用 goodness-of-fit 图、可视预测检查（VPC）和归一化预测分布误差（NPDE）对模型进行评价。基于建立的模型，通过对清除率和生物利用度的种族差异进行参数调整，模拟健康白种人受试者的 PK 曲线。PopPK 分析使用了 128 名受试者的数据。采用两室模型描述非布司他的浓度-时间曲线，包括两个贮藏吸收室和滞后时间（Tlag）。进食状态（食物）对吸收速率 ka1 和 ka2 以及 Tlag1 有显著影响，体重被确定为表观分布容积的显著协变量。在禁食和进食两种条件下，对健康中国志愿者中非布司他的 PopPK 分析成功地描述了其 PK 曲线，并强调了食物对吸收的显著影响。从模拟中得出的中国人群和白种人群之间吸收差异的潜在差异需要进一步研究。
