Krishnatry Anu Shilpa, Hanze Eva, Bergsma Tim, Dhar Arindam, Prohn Marita, Ferron-Brady Geraldine
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
qPharmetra LLC, Nijmegen, the Netherlands.
CPT Pharmacometrics Syst Pharmacol. 2022 May;11(5):556-568. doi: 10.1002/psp4.12724. Epub 2021 Oct 27.
Molibresib (GSK525762) is an investigational orally bioavailable small-molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. In the first-time-in-human BET115521 study of molibresib in patients with solid tumors, thrombocytopenia was the most frequent treatment-related adverse event (AE), QT prolongation was an AE of special interest based on preclinical signals, and gastrointestinal (GI) AEs (nausea, vomiting, diarrhea, and dysgeusia) were often observed. The aims of this analysis were the following: (i) develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model capable of predicting platelet time courses in individual patients after administration of molibresib and identify covariates of clinical interest; (ii) evaluate the effects of molibresib (and/or its two active metabolites [GSK3529246]) exposure on cardiac repolarization by applying a systematic modeling approach using high-quality, intensive, PK time-matched 12-lead electrocardiogram measurements; (iii) evaluate the exposure-response (ER) relationship between molibresib and/or GSK3529246 exposures and the occurrence of Grade 2 or higher GI AEs. Overall, the PK/PD model (including a maximal drug effect model and molibresib concentration) adequately described platelet counts following molibresib treatment and was used to simulate the impact of molibresib dosing on thrombocytopenia at different doses and regimens. ER analyses showed no clinically meaningful QT interval prolongation with molibresib at up to 100 mg q.d., and no strong correlation between molibresib exposure and the occurrence of Grade 2 or higher GI AEs. The models described here can aid dosing/schedule and drug combination strategies and may support a thorough QT study waiver request for molibresib.
莫利西布（GSK525762）是一种用于治疗晚期实体瘤的口服生物可利用小分子溴结构域和额外末端（BET）蛋白抑制剂。在莫利西布治疗实体瘤患者的首次人体BET115521研究中，血小板减少是最常见的治疗相关不良事件（AE），基于临床前信号，QT间期延长是一个特别关注的AE，并且经常观察到胃肠道（GI）AE（恶心、呕吐、腹泻和味觉障碍）。本分析的目的如下：（i）建立一个群体药代动力学（PK）/药效学（PD）模型，该模型能够预测莫利西布给药后个体患者的血小板时间进程，并确定具有临床意义的协变量；（ii）通过应用一种系统建模方法，使用高质量、密集的、PK时间匹配的12导联心电图测量，评估莫利西布（和/或其两种活性代谢物[GSK3529246]）暴露对心脏复极化的影响；（iii）评估莫利西布和/或GSK3529246暴露与2级或更高等级GI AE发生之间的暴露-反应（ER）关系。总体而言，PK/PD模型（包括最大药物效应模型和莫利西布浓度）充分描述了莫利西布治疗后的血小板计数，并用于模拟不同剂量和给药方案下莫利西布给药对血小板减少的影响。ER分析表明，莫利西布每日剂量高达100 mg时，QT间期无临床意义的延长，且莫利西布暴露与2级或更高等级GI AE的发生之间无强相关性。这里描述的模型可以辅助给药/给药方案和药物联合策略，并且可能支持对莫利西布进行全面QT研究豁免申请。
