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.

• Authors: Enrique Grande, Monica Giovannini, Eddie Marriere, Philippe Pultar, Michelle Quinlan, Xinhui Chen, Gholamreza Rahmanzadeh, Giuseppe Curigliano, Xiaoming Cui
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 87 Issue 7 Pg. 2867-2878 (07 2021) ISSN: 1365-2125 [Electronic] England
• PMID: 33300203 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Benzamides
• Imidazoles
• Neoplasm Proteins
• Pharmaceutical Preparations
• Triazines
• Digoxin
• Rosuvastatin Calcium
• capmatinib

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Benzamides (adverse effects)
• Carcinoma, Non-Small-Cell Lung
• Digoxin
• Drug Interactions
• Humans
• Imidazoles (adverse effects)
• Lung Neoplasms
• Neoplasm Proteins (metabolism)
• Pharmaceutical Preparations
• Rosuvastatin Calcium
• Triazines (adverse effects)