PII-058 - LOW SENSITIVITY OF TEPOTINIB TO DRUG-DRUG INTERACTIONS WITH CYP3A4 AND P-GP MODULATORS.

R. Strotmann¹, M. Bödding¹, A. Krebs-Brown¹, S. Haffner², C. Lüpfert¹, A. Ke³, J. Dong¹, K. Venkatakrishnan⁴; ¹Merck KGaA, Darmstadt, Germany, ²Nuvisan, Neu-Ulm, Germany, ³Certara, Princeton, NJ, USA, ⁴EMD Serono, Billerica, MA, USA.

Background: Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. For the typically elderly patient population in this indication, polypharmacy may potentially lead to drug-drug interactions (DDI) that could alter the benefit-risk profile of the anticancer treatment.

Tepotinib is subject to limited CYP-mediated metabolism, but the contribution of hepatic P-gp to biliary excretion of unchanged parent compound cannot be excluded based on in vitro data alone.

Methods: In two post-approval fixed sequence cross-over DDI studies in healthy volunteers, the impact of the strong CYP3A4 inhibitor and P-gp inhibitor itraconazole (200 mg QD as capsules, N=18, NCT05203822), and of the CYP/P-gp inducer carbamazepine (titrated up to 300 mg BID, N=18, NCT05213481) on the pharmacokinetics of single 450 mg doses of tepotinib were investigated, reflecting worst-case DDI scenarios.

Results: Co-administration of either compound led to weak drug interactions with tepotinib (geometric mean AUC ratios of 122% [90% CI: 111.48%, 134.29%] with itraconazole and 65% [90% CI: 59.80%, 70.98%] with carbamazepine). The increase in tepotinib AUC when co-administered with itraconazole is not considered clinically relevant. Based on the known PK/PD and exposure-efficacy relationships, the 35% mean tepotinib AUC reduction with carbamazepine is not expected to meaningfully change the clinical efficacy of tepotinib.

Conclusion: Together with a PBPK-based analysis of the clinical PK data, which supported a limited contribution of CYP3A of 17% to the systemic clearance of tepotinib, the contribution of hepatic P-gp to the excretion of tepotinib is estimated to be low, reinforcing the conclusion of a low risk for tepotinib to be a victim of DDIs with CYP3A/P-gp modulators.