Y. Orito,1 T. Iwasa,1 N. Uemura,2 G. Fujimoto,1 S. Yama,1 W. Gao,3 L. Caro,3 C. Fandozzi,3 T. Prueksaritanont,3 M. Anderson,3 J. Butterton,3 S. Hasegawa4; 1MSD K.K., Tokyo, Japan, 2Oita University, Oita, Japan, 3Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 4Pharmaspur Inc., Tokyo, Japan

BACKGROUND: Vaniprevir is an inhibitor of nonstructural protein 3/4A protease of hepatitis C virus. Vaniprevir inhibits OATP1B1-mediated pitavastatin uptake into MDCKII-OATP1B1 cells and inhibits sulfobromophtalein uptake into MDCKII-OATP1B3 cells. In addition, in membrane vesicles vaniprevir inhibits BCRP-mediated methotrexate transport. These data suggest the potential for vaniprevir to be a perpetrator of drug interactions with drugs whose disposition is mediated by OATP1B1, OATP1B3 and/or BCRP.
METHODS: This was an open-label, fixed-sequence, drug-drug interaction trial with vaniprevir and rosuvastatin (a substrate for OATP and BCRP) to evaluate the effect of multiple doses of vaniprevir on the pharmacokinetic parameters of a single dose of rosuvastatin in 12 healthy Japanese male subjects (ages 20-47). On Day 1, subjects received a single dose of rosuvastatin 5 mg. On Days 8 to 14, subjects received a twice-daily dose of vaniprevir 300 mg and on Day 10, a 5 mg dose of rosuvastatin was co-administered with vaniprevir in the morning.
RESULTS: The rosuvastatin AUC0- and Cmax GMR (90% CI) for the comparison of rosuvastatin + vaniprevir / rosuvastatin alone were 1.22 (1.09, 1.36) and 2.88 (2.40, 3.46). The t1/2 GM (% CV) were 8.27 (59.4) hr and 7.69 (47.5) hr, the Tmax Median [Min, Max] were 2.0 [1.0, 4.0] hr and 4.0 [2.0, 5.0] hr for rosuvastatin + vaniprevir and rosuvastatin alone.
CONCLUSION: The greater relative magnitude of increase in rosuvastatin Cmax compared to AUC with a decreased Tmax was observed when co-administered of vaniprevir. The terminal phase half-life of rosuvastatin was not significantly altered. These suggested the pre-systemic inhibition by vaniprevir on rosuvastatin uptake into the liver via OATP and efflux from the gut via BCRP.