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. Methods: 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 leastsquares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated. Results: 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. Conclusions: 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.