INTRODUCTION

Dysregulation of MET-pathway has been implicated in the pathogenesis of several human cancers including papillary renal cell carcinoma and thyroid, prostate, lung, breast, ovarian, and gastrointestinal malignancies [1-4] and in the development of resistance to chemotherapy and radiotherapy, leading to poor clinical outcomes [5-8]. The dysregulation of MET pathway may occur by different mechanisms including gene mutation, amplification, overexpression, and constitutive activation [9].
Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14 ) skipping mutations [10]. Capmatinib has also shownin vitro and in vivo activities across a range of tumor models with MET amplification and/or overexpression [11, 12]. Phase I and Phase II studies have shown a manageable safety and robust efficacy profile of capmatinib, both as monotherapy and in combination with other anticancer therapies, in patients with solid tumors [13-20].
The therapeutic dose of capmatinib is 400 mg twice daily. Following oral administration, capmatinib absorbed rapidly with time to maximum plasma concentration (Tmax) of 1-2 hours. The steady state was expected to be reach by Day 3 of consecutive twice daily dosing. Capmatinib is mainly metabolized by CYP3A4 and aldehyde oxidase.In vitro, capmatinib inhibits p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) with a IC50 of 12.0 µM and 16.4 µM, respectively. At the recommended phase II dose, capmatinib was predicted to inhibit P-gp and BCRP in vivo based on the ratio of capmatinib concentration in plasma and/or gut to Ki ([I]/Ki [R]) for P-gp and BCRP, and lead to increase in concentration of P-gp or BCRP substrates.
In clinical trials, patient populations are selected with limited or no comorbidities and concurrent medications are not permitted, follow-up period is much narrower, and the toxicities are detected earlier, so patient populations enrolled may not accurately represent the general oncology population [21]. Multiple drug therapy is also common in patients with cancer to treat their cancer or to manage the adverse effects and comorbidities. Some of these drugs are substrates of P-gp and/or BCRP [22]. Understanding the in vivo drug-drug interaction (DDI) potential of capmatinib and substrates of P-gp or BCRP will inform the safe use of capmatinib in treating cancer patients. The purpose of this study was to investigate the effect of multiple doses of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin, administered orally as a two-drug cocktail in patients with MET -dysregulated advanced solid tumors.