Drug-drug interaction profile of tepotinib with CYP3A and P-gp substrates

Abstract

Background: Tepotinib is an oral, highly selective MET inhibitor being investigated in MET-driven solid tumors. Cancer patients often receive co-medications, many of which are subject to cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp)-dependent pharmacokinetics. The potential of tepotinib to alter the exposure to such drugs was investigated in two clinical drug-drug interaction (DDI) trials. Method(s): The effect of multiple doses of the RP2D of tepotinib (500 mg QD) on the exposure of single doses of the sensitive CYP3A4 substrate midazolam and the sensitive P-gp substrate dabigatran etexilate were tested in healthy subjects, using randomized single-sequence two-period cross-over designs. The primary endpoints were Cmax and AUC for the respective probe drugs; their corresponding ratios of the geometric least-squares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated. Result(s): Most participants were male (12/12 midazolam; 19/20 dabigatran etexilate); mean age 34 years (range 19-44). There was no increase in midazolam exposure with co-administration of tepotinib (Table), suggesting that no effect on the metabolism of CYP3A is to be expected. Co-administration of tepotinib led to a 39-45% increase in dabigatran etexilate exposure. No clinically relevant effects on laboratory values, vital signs or ECG parameters were observed or reported as an AE. [Table presented] Conclusion(s): After multiple doses of tepotinib at the RP2D (500 mg QD), there was no relevant exposure increase of the sensitive CYP3A substrate midazolam, and a < 2-fold mean exposure increase of the sensitive P-gp substrate dabigatran etexilate, indicating that tepotinib is a weak P-gp inhibitor. Tepotinib was considered safe and well tolerated in these studies of healthy volunteers. In summary, the potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the intended posology is considered low. Clinical trial identification: NCT03492437 and NCT03628339. Editorial acknowledgement: Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cusco, PhD of Bioscript Group (Macclesfield, UK). Legal entity responsible for the study: Merck Healthcare KGaA. Funding(s): Merck Healthcare KGaA. Disclosure: O. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. R. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.Copyright © 2019 European Society for Medical Oncology