贝伊曲丹（Welireg，Merck & Co, Inc.）是一种口服高效的缺氧诱导因子（HIF）2α抑制剂，已获批用于治疗一定患有冯·希珀·林道（VHL）疾病相关的肾细胞癌（RCC）、中枢神经系统血管占位病变和胰腺神经内分泌肿瘤（pNET）的患者。药物主要通过多态性尿嘧啶二磷酸葡萄糖醛酸转移酶（UGT）2B17和细胞色素（CYP）2C19代谢。我们使用NONMEM® v7.3构建了一个人群药代动力学（PK）模型，该模型基于3个临床药理学（食物影响、制剂桥接、基因型/种族影响）和2个临床（RCC和其他实体肿瘤的一期剂量递增/扩展；VHL患者的二期研究）研究的人口学/PK数据。综合研究的中位数年龄（范围）为55岁（19-84），体重为73.6公斤（42.1-165.8）。贝伊曲丹在血浆中的PK特性通过线性二室模型、一级吸收和消除得到很好的确定。对于VHL患者，预测的几何均值（%变异系数[CV]）明显清除（CL/F）为7.3 L/h（51%），明显分布体积（Vd/F）为130 L（35%）；半衰期为12.39小时（42%）。根据个体共变量的年龄、性别、种族、人种、体重、轻度/中度肾功能障碍或轻度肝功能障碍，贝伊曲丹PK没有临床相关性差异。在该模型中，预估双重UGT2B17和CYP2C19差异代谢物贫乏者（PM）与UGT2B17广泛代谢者和CYP2C19非-PM患者相比，贝伊曲丹浓度-时间曲线下的面积（AUC）高出3.2倍。此人群PK分析使我们能够对贝伊曲丹药代动力学特征进行综合评估，并结合个体共变效应和总体-亚群进行标示。

Belzutifan (Welireg, Merck & Co, Inc.) is an oral, potent inhibitor of hypoxia-inducible factor (HIF) 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM® v7.3, based on demographics/PK data from 3 clinical pharmacology (food effect, formulation bridging, genotype/race effect) and 2 clinical (phase 1 dose escalation/expansion in RCC and other solid tumors; phase 2 in VHL patients) studies. Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear 2-compartment model with first-order absorption and elimination. For VHL patients, the predicted geometric mean (% coefficient of variation [CV]) apparent clearance (CL/F) was 7.3 L/hr (51%), apparent total volume of distribution (Vd/F) was 130 L (35%); and half-life was 12.39 hours (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.This article is protected by copyright. All rights reserved.