J. Lettieri,1 A. Ajavon,1 Z. Jirakova,2 I. Sturm,2 M. Gerisch3; 1Bayer HealthCare, Whippany, NJ, 2Bayer Pharma AG, Berlin, Germany, 3Bayer Pharma AG, Wuppertal, Germany

BACKGROUND: Regorafenib is an oral multi-kinase inhibitor approved for the treatment of colorectal cancer and gastrointestinal (GI) stromal tumors. REG undergoes extensive and complex metabolism, including oxidation by CYP3A4 to M-2 (which is further metabolized to M-5) and glucuronidation by UGT1A9 to M-7. M-2 and M-5 are major metabolites that are pharmacologically active. Both REG and M-2 may undergo enterohepatic cycling (EHC). Suppression of GI flora by antibiotics such as Neomycin may prevent the cleavage of REG and M-2 conjugates, thereby lowering reabsorption and overall exposure. The aim of this study was to evaluate the PK of REG and metabolites in plasma and urine in subjects with and without N pretreatment.
METHODS: This was an open-label, two-period sequential treatment study in 27 healthy males. In Period 1, a single 160 mg REG dose was followed by a 14-day washout. In Period 2, a single 160 mg REG dose was given after a 5-day treatment with 3 g/day of N. Blood was collected up to 192 hrs after each REG dose. Urine was collected after each REG dose up to 72 hrs. Samples were assayed by LC/MS/MS.
RESULTS: Following pretreatment with N, there was no relevant change in REG mean exposure (<10% decrease) but a >77% decrease in both mean M-2 and M-5 exposure. N had no effect on urinary excretion of REG glucuronide M-7 but resulted in a 73% decrease in urinary excretion of the M-2 glucuronide (M-8). No change in elimination half-life for REG and its metabolites was observed.
CONCLUSION: N had no relevant effect on REG, but significantly reduced M-2 and M-5 exposure. Decreased M-2 could be a result of reduced EHC, due to inhibition of bacterial β-glucuronidase activity. Effects on M-5 may be the result of the lower M-2 exposure. The clinical significance of these findings is unknown but may result in decreased efficacy of REG.