PII-083 - PHARMACOGENOMIC ANALYSIS OF THE PHARMACOKINETIC ENDPOINTS FROM A DRUG-DRUG INTERACTION STUDY OF ENCORAFENIB IN COMBINATION WITH BINIMETINIB USING THE INJE COCKTAIL IN CANCER PATIENTS.

C. Tran¹, M. Reddy², L. Wollenberg², J. Piscitelli²; ¹UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, ²Pfizer, Inc..

Background: Drug-drug interaction (DDI) studies are commonly conducted during drug development, and pharmacogenomic testing can be added to rule out drug-drug-gene interactions which could influence the results.1 Based on in vitro studies conducted with encorafenib (a mutant BRAF kinase inhibitor), a DDI study was designed to evaluate the effect of encorafenib in combination with binimetinib on single oral dose PK of the 5 specific CYP substrates included in the Inje Cocktail.2,3 This cocktail includes losartan (CYP2C9), midazolam (CYP3A4), caffeine (CYP1A2), dextromethorphan (CYP2D6), and omeprazole (CYP2C19).3 A pharmacogenomic analysis was conducted to assess correlations between the pharmacokinetics (PK) and genotype to determine if metabolizer status was relevant to DDI study results interpretation.

Methods: This study was conducted in patients with BRAF V600-mutant unresectable or metastatic melanoma or other advanced solid tumors. Due to encorafenib autoinduction which causes lower concentrations at steady state compared to the first day of dosing and potential inhibition (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) and induction (CYP2C9 and CYP3A4) based on in vitro data, patients received a single oral dose of cocktail substrates on Day -7, 1 and 14 to assess potential DDI at both single dose and steady-state encorafenib concentrations. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. A blood sample was collected at screening to assess genotype. PK collection of plasma and urine was conducted from 0-8 hours on Day -7, 1 and 14. Noncompartmental analysis for plasma and urine was performed.

Results: The CYP substrate PK parameters subset by metabolizer status for each study day are presented in Figure 1. For context, another abstract submitted to this congress by Piscitelli et al showed that the only clinically significant DDI was strong induction of CYP3A4 on Day 14 (82% decrease in midazolam AUClast).

Conclusion: This analysis indicates that there was no clinically significant trend between metabolizer status and PK endpoints for all 5 analytes. Losartan (CYP2C9) and caffeine (CYP1A2*F) had slight differences, but no definitive conclusions could be made due to high variability and a limited number of participants for uncommon genotypes.