A phase I study to determine the effect of regorafenib (REG) on the pharmacokinetics (PK) of substrates of P-glycoprotein (P-gp; digoxin) and breast cancer resistant protein (BCRP; rosuvastatin) in patients with advanced solid tumors

Background

REG is an oral multikinase inhibitor approved for the treatment of mCRC and advanced GIST. In vitro data showed that REG has an inhibitory effect on BCRP and P-gp transporters. A study was designed to evaluate the effect of REG on the PK of digoxin (P-gp substrate) and rosuvastatin (BCRP substrate).

Methods

This was an open-label, non-randomized, 2-parallel group study to compare the PK of the P-gp substrate digoxin (group A) and BRCP substrate rosuvastatin (group B) with and without REG. Oral REG 160 mg QD was administered in 28-day cycles (3 weeks on/1 week off). On pre-cycle Day -7 and cycle 1 Day 15, patients received a single oral dose of digoxin (0.5 mg, group A) or rosuvastatin (5 mg, group B), and serial plasma samples were collected for PK analysis.

Results

42 patients were treated and 30 patients were evaluable for PK analysis (17 in group A; 13 in group B). There was no relevant change in mean AUC_(0–24) and C_max of digoxin (

Conclusions

REG had no effect on the PK of the P-gp substrate digoxin. Co-administration of REG with the BCRP substrate rosuvastatin resulted in a 3.8-fold increase in mean exposure (AUC) and a 4.6-fold increase in C_max of rosuvastatin indicating that REG may increase the plasma concentrations of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP substrates. The safety profile was consistent with the known safety profile of REG.

Clinical trial identification

NCT02106845

Legal entity responsible for the study

Bayer

Funding

Bayer

Disclosure

A. Cleton: Stock ownership: AstraZeneca, Bayer, Pfizer. Other substantive relationships: Bayer (employee). F. Huang, K. Graudenz, Z. Trnkova: Other substantive relationships: Bayer (employee). U. Mueller: Advisory board: Bayer. Other substantive relationships: ClinStat GmbH (employee). I. Sturm: Stock ownership: Bayer. Other substantive relationships: Bayer (employee). All other authors have declared no conflicts of interest.