Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model
Molibresib (GSK525762) is an investigational, orally available small-molecule inhibitor targeting bromodomain and extraterminal (BET) proteins, developed for the treatment of advanced solid tumors. Its clinical evaluation began with the first-in-human (FTIH) study BET115521, which was conducted in two parts: Part 1, a dose-escalation phase involving 94 patients with NUT midline carcinoma and other solid tumors, and Part 2, an expansion cohort comprising 99 patients with various solid tumor types.
Molibresib is primarily metabolized by cytochrome P450 3A4 enzymes, generating two major active metabolites that exhibit potency equivalent to the parent compound. These metabolites are quantified as a combined entity, referred to as the active metabolite composite (GSK3529246), following full interconversion.
Pharmacokinetic (PK) data from the FTIH study revealed a time-dependent decrease in molibresib exposure, particularly at higher doses. This decline in drug levels was accompanied by a modest increase in the concentrations of GSK3529246, suggesting autoinduction of molibresib metabolism—a phenomenon subsequently confirmed in vitro.
To characterize this behavior, a semimechanistic population PK model with a liver compartment was developed. This model accurately captured the autoinductive clearance of molibresib and described the PK profiles of both molibresib and its active metabolites. Covariate analysis identified body weight as a significant factor influencing the volume of distribution for both compounds. Additionally, elevated aspartate aminotransferase (AST) levels were associated with reduced clearance of GSK3529246.
This modeling framework enables simulation of individual patient exposures based on clinical covariates and supports future efforts in optimizing dosing strategies and conducting exposure-response analyses.