PBPK Modelling of PROTACs: Learnings from ARV-110 as a Case Example.

The study presents a comprehensive evaluation of physiologically-based pharmacokinetic (PBPK) modeling for Proteolysis Targeting Chimeras (PROTACs), using ARV-110 (Bavdegalutamide) as a case example. We sought to develop a PBPK model that accurately predicts the human pharmacokinetics (PK) of ARV-110 and began with a bottom-up approach to predict ARV-110 PK in mice and rats using available ADME and physicochemical data. Owing to the observed in vitro-in vivo extrapolation (IVIVE) gaps in clearance, the published in vivo data was used for refinement, resulting in a middle-out PBPK model bridging this discrepancy. PBPK predictions were extrapolated to human and validated against observed clinical PK for single and multiple doses in healthy volunteers and cancer patients revealing IVIVE gaps for human clearance. Similar to rodents, a middle-out modeling approach was then used to refine the human PBPK prediction. This model effectively captured plasma drug concentration-time profiles reported for preclinical and clinical studies, including studies involving impact of food and drug-drug interactions with itraconazole and esomeprazole. All observed human concentrations were within 5th and 95th percentile of predictions and PK parameters were within two-fold of the observed in vivo data. Following administration of a single dose (280 mg) of ARV-110, the observed vs. predicted AUC