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: In the analysis, the effect of rivoceranib on the PK of CYP1A2 substrates did not appear to be clinically significant. Rivoceranib may inhibit the metabolism of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates, suggesting that dose adjustment of substrates of these CYP isozymes and/or cautiously monitoring patients’ adverse events may be needed when they are co-administered with rivoceranib. Citation Format: Janelle Weyer, Xianzhang Meng, Jennifer Lee, Joseph Reitano, Vinoo Urity, Cheol-Hee Park, Bill Strickland, Jan Van Tornout, Seong Jang. Evaluation of the effect of rivoceranib on the pharmacokinetics of cytochrome P450 enzyme substrates in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT273.
Introduction: Vascular endothelial growth factor receptor 2 (VEGFR-2) is a key regulator of tumor angiogenesis that is highly expressed in several tumor types and is a known target for anti-cancer therapy. Yet the clinical use of VEGFR-2 inhibitors has been challenged by limited efficacy and various side effects, potentially due to the low selectivity of these TKIs for VEGFR-2. Thus, potent VEGFR-2 inhibitors with improved selectivity are needed. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR-2. A comparison of the potency and selectivity of VEGFR-2 inhibitors can provide a rationale for selecting a specific TKI for anticancer therapy in the clinic. Methods: Binding of rivoceranib to VEGFR-2 was determined on a Biacore T200. The affinity constant (KD) was derived from the association and dissociation rate constants. Inhibitory potency of rivoceranib and 10 FDA-approved reference inhibitors on kinase enzyme activity was determined using mobility shift assays (MSA) or immobilized metal ion affinity particle (IMAP) assays. The half-maximum inhibitory activity (IC50) of the 11 inhibitors on VEGFR-2 was determined in 10-point dose-response curves. The selectivity of the inhibitors was determined on 270 wild-type kinases at a fixed concentration of each inhibitor. Rivoceranib was tested at 10- and 100-times IC50 (160 nmol/L and 1.6 µmol/L). Reference inhibitors were tested at 1 µmol/L (35 to 1056-times IC50). Results: Rivoceranib had a KD of 3 nmol/L on VEGFR-2. In enzyme activity assays, rivoceranib had intermediate potency compared with the 10 reference inhibitors, with a VEGFR-2 kinase inhibition IC50 value of 16 nmol/L. Analysis of the residual activity of the panel of 270 kinases in the presence of rivoceranib or the reference inhibitors showed wide variation in selectivity for VEGFR-2, with rivoceranib identified as the most selective inhibitor (activity of 16 additional kinases inhibited by >50% at 1.6 µmol/L). Tivozanib, the most potent VEGFR-2 inhibitor, displayed greater than 50% inhibitory activity against more than 70 additional kinases. Sunitinib was identified as the least selective inhibitor included in this study, inhibiting 125 additional kinases by >50%. Conclusion: Variations in selectivity among TKIs with similar anti-VEGFR-2 potency can help explain differences in their clinical toxicity profiles, which may be partially due to variant inhibitory effects against TKIs other than VEGFR-2. This comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with the poor selectivity of currently available VEGFR-2 inhibitors. Rivoceranib is under ongoing investigation as monotherapy and in combination with chemotherapy in various tumor types. Citation Format: Seong Jang, Bill Strickland, Lynda Finis, Jeffrey J. Koojiman, Janneke J. Melis, Guido J. Zaman, Jan V. Tornout. Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4014.
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