5455 - Bioavailability of tepotinib: impact of omeprazole and food

Background

Acid-inhibitory drugs (e.g. proton pump inhibitors - PPIs) increase intragastric pH, which may decrease solubility, bioavailability, and efficacy of oral cancer drugs. Furthermore, polypharmacy in cancer patients is common and different requirements for treatment with or without food can impact compliance. Tepotinib is an oral, highly selective MET inhibitor being investigated in patients with solid tumors with MET dysregulation (METex14 mutations or MET amplification). In the pivotal clinical trial, tepotinib has been administered with breakfast; this represents the intended posology. Tepotinib has pH-dependent low solubility, suggesting that food intake and/or co-administration with a PPI may impact bioavailability. We investigated the effects of the PPI omeprazole and food on tepotinib.

Methods

In a 3-period, cross-over study, healthy volunteers (n = 12) received 500 mg/day tepotinib as a single dose 30 mins after a continental breakfast (treatment A) and co-administered on Day 5 after receiving omeprazole (40 mg QD for 5 days) under fasted conditions (treatment B) and after a continental breakfast (treatment C). The impact of omeprazole on the AUC_0-t, AUC_0-∞, and C_max of tepotinib under fed conditions was evaluated comparing treatments A and C; corresponding ratios of the geometric least-squares means (GLSM) (90% CI) were reported. In a separate study, food effect was investigated in healthy volunteers (n = 12) by administering single doses of 500 mg tepotinib under fasted state and after a high-fat, high-calorie breakfast.

Results

In the first study, there was a negligible effect of omeprazole co-administration on the bioavailability of tepotinib under fed conditions. The GLSM ratios (90% CI) for treatment C/A were 1.09 (1.01, 1.17) for AUC_0-t; 1.10 (1.02, 1.19) for AUC_0-∞; and 1.04 (0.93, 1.17) for C_max. In the second study, the ratio (90% CI) of “high-fat” /”fasted” for tepotinib AUC_0-∞ was 1.87 (1.64, 2.13) and for C_max was 2.37 (2.16, 2.59).

Conclusions

The intended posology of tepotinib, i.e. with food, is in agreement with the moderate food effect (approximately 2-fold increase in exposure of tepotinib). When tepotinib is administered at 500 mg/day together with food, co-administration of PPI is not expected to have clinically relevant drug interactions.

Clinical trial identification

NCT03531762 and NCT03629223.

Editorial acknowledgement

Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK).

Legal entity responsible for the study

Merck Healthcare KGaA.

Funding

Merck Healthcare KGaA.

Disclosure

R. Strotmann: 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. N. Mammasse: Full / Part-time employment: Merck Healthcare KGaA. Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.