Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a two-drug cocktail in patients with MET-dysregulated advanced solid tumors: A phase I, multicenter, open-label, single-sequence drug-drug interaction study.

AIMS Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic non-small cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumors. METHODS This was a multicenter, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumors on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction (DDI) assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated. RESULTS Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% CI) of AUCinf and Cmax for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% CI) of AUCinf and Cmax for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (AEs; ≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral edema and pyrexia. Most frequent Grade 3/4 AEs (≥5%) were anemia, pulmonary embolism, asthenia, dyspnea, nausea and vomiting. CONCLUSION This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant DDI potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.