Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET‐dysregulated solid tumours

Abstract

Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety.Methods: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail.Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine.After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator.Results: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (C max ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUC inf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUC last ), respectively, with no change in C max . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. Conclusion:The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.The authors confirm that the Principal Investigator for this paper is Dr Morten Mau-Sorensen and that he had direct clinical responsibility for the patients.