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.