Abstract 3016: Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers

Abstract Background: Tucatinib is a potent, highly selective HER2 tyrosine kinase inhibitor in development for the treatment of patients with HER2+ metastatic breast cancer. In vitro metabolism studies suggest that drug metabolizing enzymes CYP2C8 and CYP3A play a role in tucatinib metabolism. Tucatinib exhibits competitive inhibition of CYP2C8, CYP2C9, CYP3A, and P-gp, and metabolism-dependent inactivation of CYP3A in vitro. ONT-380-012 was a clinical drug interaction study conducted to evaluate the magnitude of potential enzyme and transporter interactions for tucatinib (both as a victim and perpetrator), and the safety of healthy subjects when administered tucatinib doses at therapeutic levels (300 mg BID). Methods: Healthy volunteers (n=116) at multiple centers were enrolled in the study. Parts A-C evaluated the effects of a strong CYP2C8 inhibitor (gemfibrozil), a strong CYP3A inhibitor (itraconazole), and a CYP3A/CYP2C8 inducer (rifampin) on single-dose tucatinib (300 mg) PK. Parts D and E assessed the effects of steady-state tucatinib (300 mg BID) on single-dose PK of substrate probes for CYP2C8 (repaglinide), CYP2C9 (tolbutamide), CYP3A (midazolam), and P-gp (digoxin). Plasma samples were collected for PK analysis and drug concentrations were measured using validated LC-MS/MS methods. Results: A strong CYP3A inhibitor (itraconazole) increased tucatinib AUCinf and Cmax 1.3-fold. A CYP3A/CYP2C8 inducer (rifampin) decreased tucatinib AUCinf and Cmax 48% and 37%, respectively. A strong CYP2C8 inhibitor (gemfibrozil) increased tucatinib AUCinf and Cmax 3.1- and 1.6-fold, respectively. Tucatinib increased the AUCinf and Cmax of the CYP3A substrate (midazolam) 5.7- and 3.0-fold, respectively, the AUCinf and Cmax of the CYP2C8 substrate (repaglinide) 1.7-fold, and the AUCinf of the P-gp substrate (digoxin) 1.5-fold. Tucatinib had no impact on the PK of the CYP2C9 substrate (tolbutamide). Overall, tucatinib was well tolerated in healthy volunteers when administered 300 mg BID. Conclusions: Together, these data indicate tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A. Tucatinib was found to be a strong inhibitor of CYP3A, a weak inhibitor of CYP2C8 and P-gp, and had no impact on CYP2C9-mediated metabolism in vivo. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Hao Sun, JoAl Mayor, Luke Walker, Christopher J. Endres. Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3016.