ZEPATIER™ (elbasvir and grazoprevir) tablets

Mechanism of Action A fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus.
Pharmacodynamics (PD) At therapeutic concentration both elbasvir and grazoprevir do not prolong QTc to any clinically relevant extent.
Pharmacokinetics (PK) Elbasvir pharmacokinetics were similar in both healthy and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.

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.

PK-PD Analysis Not reported.
Population PK Elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age.

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.


Special Populations Exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.

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 HCV infected, non-cirrhotic subjects.

Drug Interactions Elbasvir and grazoprevir are substrates of CYP3A. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations. 17 Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.

Source : https://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf


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