Physiologically Based Pharmacokinetic Model to Assess the Drug-Drug-Gene Interaction Potential of Belzutifan in Combination With Cyclin-Dependent Kinase 4/6 Inhibitors.

Abstract

Purpose: Belzutifan is a novel treatment for von Hippel-Lindau-associated cancers and is being evaluated in clinical trials for the treatment of renal cell carcinoma in combination with the cyclin-dependent kinase 4/6 inhibitors abemaciclib (ClinicalTrials.gov identifier: NCT04627064) and palbociclib (ClinicalTrials.gov identifier: NCT05468697). Belzutifan is metabolized via CYP2C19 and UGT2B17 and is a weak inducer of CYP3A. Induction of CYP3A is predicted to have a greater effect in dual CYP2C19/UGT2B17 poor metabolizers (PMs) relative to normal metabolizers (referred to as extensive metabolizers [EMs] in Simcyp). Our objective was to assess the drug-drug-gene interaction (DDGI) potential of belzutifan when coadministered with the CYP3A substrates abemaciclib and palbociclib in individuals with varying CYP2C19/UGT2B17 phenotypes.

Methods: Physiologically based pharmacokinetic (PBPK) models for belzutifan, abemaciclib, and palbociclib were constructed in Simcyp v.21 and confirmed using data from US Food and Drug Administration reviews and previous publications. Virtual trials evaluating the area under the concentration-time curve from time 0 to infinity (AUC_0-inf) of single-dose palbociclib (125 mg) or abemaciclib (200 mg) alone and after 7 days of belzutifan (120 mg once daily) were simulated in healthy volunteers with differing CYP2C19/UGT2B17 phenotypes.

Results: Compared with dual CYP2C19/UGT2B17 EMs, predicted belzutifan exposure increased approximately 4.4-fold in dual PMs. Belzutifan decreased the AUC_0-inf of abemaciclib by 24.3% and 52.2% in dual EMs and dual PMs, respectively, with the relative potency-adjusted unbound AUC_0-inf decreasing by 23.5% and 47.9%. Similarly, belzutifan decreased the AUC_0-inf of palbociclib by 13.2% and 36.8% in dual EMs and dual PMs, respectively.

Conclusion: Our simulations predict that belzutifan decreases the exposure of combination therapies metabolized via CYP3A, with the severity of interaction dependent on CYP2C19 and UGT2B17 phenotypes.