Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. This work aimed to investigate the potential for drug-drug interactions with strong inhibitors and inducers of both cytochrome P450 (CYP) 3A4/5 and P-glycoprotein (P-gp) with tepotinib. Two clinical studies were conducted to investigate the effect of the strong CYP3A4/P-gp inhibitor itraconazole (200 mg once daily) (NCT05203822) and the strong CYP3A4/P-gp inducer carbamazepine (titrated to 300 mg twice daily) (NCT05213481) on the pharmacokinetics of single dose tepotinib 500 mg (450 mg active moiety) in healthy participants. An investigational physiologically-based pharmacokinetic model, developed leveraging mass balance data, was used to evaluate the mechanisms underlying these interactions. Itraconazole increased tepotinib area under the curve extrapolated to infinity (AUC) by 22% (geometric mean ratio [GMR] 122.35%; 90% confidence intervals [CIs] 111.48%, 134.29%), but had no effect on tepotinib C (GMR 101.53%, 90% CI: 94.00%, 109.67%). Carbamazepine decreased tepotinib AUC by 35% (GMR 65.15%, 90% CI: 59.80%, 70.88%) and C by 11% (GMR 89.31%, 90% CI: 83.43%, 95.60%). None of these changes were considered to be clinically relevant. Single doses of tepotinib were considered safe and well tolerated in both studies. The observed pharmacokinetic interactions were consistent with a low (~17%) contribution of CYP3A4 to tepotinib metabolism without a relevant role for P-gp mediated biliary secretion. The potential of tepotinib to be a victim of modulators of both CYP3A4 and P-gp at the intended posology is considered low.