Abstract CT273: Evaluation of the effect of rivoceranib on the pharmacokinetics of cytochrome P450 enzyme substrates in healthy volunteers

Introduction: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. Rivoceranib is metabolized in the liver mostly by cytochrome P450 (CYP)3A4/5, with minor contributions from CYP2D6, CYP2C9, and CYP2E1. In vitro and in vivo studies suggest rivoceranib may interact with various CYP substrates, including CYP 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. The purpose of study is to evaluate the effect of rivoceranib on the pharmacokinetics (PK) of various CYP substrates. Methods: This study was an open-label, 2-treatment, fixed-sequence drug-drug interaction phase 1 study evaluating the impact of multiple oral doses of 700 mg rivoceranib on the single-dose PK of CYP enzyme substrates administered in a 5+1 probe cocktail (caffeine [CYP1A2], S- and R-warfarin [CYP2C9] + vitamin K, omeprazole [CYP2C19], dextromethorphan [CYP2D6], and midazolam [CYP3A]) in healthy volunteers (N=32). On day 1, volunteers received a single dose of the 5+1 cocktail comprising 200 mg caffeine, 10 mg S- and R-warfarin with 10 mg vitamin K, 40 mg omeprazole, 30 mg dextromethorphan, and 2 mg midazolam. Blood samples were collected predose on day 1 and up to 120 hours post-dose for PK analyses of the substrates in the 5+1 cocktail. On days 6 to 15, volunteers received 700 mg rivoceranib once daily for 10 consecutive days with a single dose of the 5+1 cocktail administered on day 11. Blood samples were collected predose on day 11 and up to 120 hours post cocktail dosing (day 16) for PK analyses. Each dosing was under fasted conditions. There was a washout period of 5 days between Day 1 dosing and the first rivoceranib dose on Day 6; the 2 cocktail dosings were spaced by 10 days. Results: Rivoceranib reduced caffeine AUC0-inf by 15%, and did not change caffeine Cmax, indicating a minimal effect of rivoceranib on the PK of CYP1A2 substrates. S-warfarin and R-warfarin AUC0-inf increased by 68% and 32%, respectively, and Cmax by 19% and 15%, respectively, when co-administered with rivoceranib, indicating rivoceranib weakly inhibits CYP2C9. Rivoceranib appeared to act as a moderate inhibitor of CYP2C19, increasing omeprazole AUC0-inf 3.3-fold and increasing Cmax 2-fold. Dextromethorphan metabolism (CYP2D6) was inhibited, with a 2- to 2.7-fold increase in dextromethorphan exposure. Rivoceranib appeared to moderately inhibit midazolam metabolism by CYP3A4, with 2.4- to 2.8-fold increases in midazolam exposures. Conclusion: I