Molibresib (GSK525762) is an investigational orally bioavailable small molecule bromodomain and extra-terminal (BET) protein inhibitor for the treatment of advanced solid tumors. In the first-time-in-human (FTIH) 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: i) develop a population pharmacokinetic/pharmacodynamic (PK/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 utilizing high quality, intensive, PK time-matched 12-lead electrocardiogram (ECG) measurements ; iii) evaluate the exposure-response (ER) relationship between molibresib and/or GSK3529246 exposures and the occurrence of ≥ Grade 2 GI AEs. Overall, the PK/PD model (including an E model and molibresib concentration) adequately described platelet counts following molibresib treatment and was utilized 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 QD, and no strong correlation between molibresib exposure and the occurrence of ≥ Grade 2 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.
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