The pharmacokinetics of regorafenib, M-2, and M-5 were eva luated in 10 patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
 
Drug-drug interactions

In vitro screening on cytochrome P450 enzymes: In vitro studies with human hepatic microsomes or recombinant enzymes showed that regorafenib competitively inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19 with R1 values > 1.1; M-2 inhibits CYP2C9, CYP2C8, CYP3A4, and CYP2D6 with R1 values > 1.1 and M-5 inhibits CYP2C8 with a R1 value > 1.1. In vitro studies with primary human hepatocytes showed that regorafenib is not expected to induce CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
 
In vitro screening on uridinediphosphateglucuronosyltransferases: In vitro studies with human hepatic microsomes showed that regorafenib, M-2, and M-5 competitively inhibits UGT1A9 and UGT1A1 at therapeutically relevant concentrations.
 
In vitro screening on transporters: In vitro data showed that regorafenib is an inhibitor of ABCG2 (Breast Cancer Resistance Protein) and ABCB1 (P-glycoprotein).
 
Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see Drug Interactions (7.1)].
 
Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy menreceived a single 160 mg dose of Stivarga alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
 
Effect of regorafenib on a substrate of UGT1A1 substrates: Eleven patients received irinotecan-containing combination chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga.
 
13 NONCLINICAL TOXICOLOGY
 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
 
Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicityin in vitro or in vivo assays; however, a major human active metabolite of regora