March 2016 – Drug and Device Digest

Elbasvir median Tmax is at 3 hours (range of 3 to 6 hours); grazoprevir median Tmax is at 2 hours (range of 30 minutes to 3 hours) in HCV-infected subjects. Steady-state Cmax for elbasvir and grazoprevir are 121 ng/mL and 165 ng/mL, respectively. Corresponding values for AUC24 are 1920 ng.hr/mL and 1420 ng.hr/mL, respectively.

Elbasvir AUC0-inf and Cmax decreases by approximately 11% and 15%, respectively with high fat food in healthy subjects, whereas AUC0-inf and Cmax of grazoprevir increases by approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food.

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively.

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma

Elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males

Elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans

Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. Elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. Grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCVinfected, non-cirrhotic subjects.