Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2‐drug cocktail in patients with MET‐dysregulated advanced solid tumours: A phase I, multicentre, open‐label, single‐sequence drug–drug interaction study

Abstract

Aims Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall 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 tumours. Methods This was a multicentre, 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 tumours 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 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% confidence interval) of area under the concentration–time curve from time zero to infinity and maximum concentration 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% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting. Conclusion This study demonstrated that capmatinib is an inhibitor of P‐gp and BCRP transporters, with clinically relevant drug–drug interaction potential. Capmatinib was well‐tolerated and no unexpected safety concerns were observed.

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

“…The safety of capmatinib was consistent with previously reported data 17,25,26 . Capmatinib demonstrated a manageable toxicity profile in this population of 37 patients with MET ‐dysregulated advanced solid tumours.…”

“…However, when the effect of capmatinib on CYP3A TDI was assessed using human hepatocytes suspended in plasma, no CYP3A TDI was observed. We have previously shown that capmatinib is an inhibitor and a substrate of P‐gp 17 . It is possible that the P‐gp dependent efflux could limit the entry into the hepatocytes, with less access to the enzymes, thus lowering the metabolism and also the inhibition potential.…”

“…Recently, we showed that capmatinib is an inhibitor of p‐glycoprotein (P‐gp) and breast cancer resistant protein (BCRP) transporters, with clinically relevant drug‐drug interaction (DDI) potential 17 . In addition, the in vitro investigation of the DDI potential of capmatinib on the cytochrome CYP450 enzymes indicates that the substrates of CYP1A2 or CYP3A are most likely to be affected by capmatinib in a clinical setting.…”

“…Recently, we showed that capmatinib is an inhibitor of p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) transporters, with clinically relevant drug-drug interaction (DDI) potential. 17 In addition, the in vitro investigation of the DDI potential of capmatinib on the cytochrome CYP450 enzymes indicates that the substrates of CYP1A2 or CYP3A are most likely to be affected by capmatinib in a clinical setting. Furthermore, in vitro data suggest that capmatinib, at clinically relevant concentrations, reversibly and in a time-dependent manner inhibits substrate reactions catabolised by cytochrome P450 (CYP) 1A2 (Ki = 9.2 μM, KI, u = 9.2 μM, kinact = 0.03 min À1 ) and CYP3A (Ki = 3.6 μM, KI, u = 9.8 μM, kinact = 0.03 min À1 ; Novartis data on file).…”

Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

“…This is because the distribution phases for both compounds end well before that. 15,16 Given the well-understood PK of these compounds, 30 hours of monitoring provides exposure estimates of sufficient accuracy to quantify and categorize the magnitude of the drug interaction(s) and make reasonable dosing recommendations. Second, due to the progressive nature of the disease, and patients' rapidly increasing morbidity over time, crossover study design with multiple periods and intercurrent washouts is not feasible and inappropriate.…”