PII-099 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL TO ASSESS THE DRUG-DRUG-GENE INTERACTION POTENTIAL OF BELZUTIFAN IN COMBINATION WITH CYCLIN-DEPENDENT KINASE 4/6 INHIBITORS IN HEALTHY VOLUNTEERS.

D. Meiman, T. Shugg, T. Skaar, S. Quinney; Indiana University, Indianapolis, IN, USA.

Background: Belzutifan is a novel treatment for several 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 and palbociclib. Belzutifan is metabolized via UGT2B17 and CYP2C19 and is a weak inducer of CYP3A4, with greater induction predicted in dual UGT2B17/CYP2C19 poor metabolizers (PMs). Our objective was to assess the drug-drug-gene interaction potential of belzutifan when co-administered with the CYP3A4 substrates abemaciclib and palbociclib in individuals with varying UGT2B17/CYP2C19 phenotypes.

Methods: Physiologically based pharmacokinetic (PBPK) models for belzutifan, abemaciclib, and palbociclib were constructed in Simcyp V21 and confirmed using data from FDA reviews and prior publications.[1-3] Virtual trials evaluating the AUC0-inf of single dose palbociclib (125 mg) or abemaciclib (200 mg) alone and following 7 days of belzutifan (120 mg once daily) were simulated in healthy volunteers with differing UGT2B17/CYP2C19 phenotypes.

Results: Compared to dual UGT2B17/CYP2C19 extensive metabolizers (EMs), belzutifan exposure increased approximately 4.4-fold in dual PMs. Belzutifan decreased the AUC0-inf of abemaciclib by 24.3% and 52.2% in dual EMs and dual PMs, respectively, with the relative potency-adjusted unbound AUC[2] decreasing by 17.3% and 40.7%. Similarly, belzutifan decreased the AUC0-inf of palbociclib by 13.2% and 36.8% in dual EMs and dual PMs, respectively.

Conclusion: Belzutifan has the potential to decrease the exposure of combination therapies metabolized via CYP3A4, with the interaction dependent on UGT2B17/CYP2C19 phenotype.

1. Merck Sharp Dohme. Welireg (belzutifan) [Multi-Discipline Review]. U.S. Food and Drug Administration website. Approved August 13, 2021. Accessed April 6, 2022.
2. Posada, M. M., Morse, B. L., Turner, P. K., Kulanthaivel, P., Hall, S. D., & Dickinson, G. L. (2020). Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling. J. Clin. Pharmacol. 60(7), 915–930.
3. Yu, Y., Loi, C. M., Hoffman, J., & Wang, D. (2017). Physiologically Based Pharmacokinetic Modeling of Palbociclib. J. Clin. Pharmacol. 57(2), 173–184.