The pharmacokinetic properties of the components of VOSEVI are provided in Table 4. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite GS-331007, velpatasvir, and voxilaprevir are provided in Table 5.

Sofosbuvir and GS-331007 AUC0–24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=137), velpatasvir AUC0–24 and Cmax were 41% lower and 39% lower, respectively, in HCV-infected subjects. Relative to healthy subjects (N=63), voxilaprevir AUC0–24 and Cmax were both 260% higher in HCV-infected subjects.

Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg in healthy volunteers. However, velpatasvir exhibited near dose-proportional increase in exposures 25 mg to 150 mg in HCV-infected patients. Voxilaprevir AUC increases in a greater than proportional manner over the dose range of 100 to 900 mg when administered with food.

Specific Populations

Pediatric Patients: The pharmacokinetics of VOSEVI in pediatric patients has not been established [see Use in Specific Populations (8.4)].

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 85 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, velpatasvir, or voxilaprevir [see Use in Specific Populations (8.5)].

Patients with Renal Impairment:

The pharmacokinetics of sofosbuvir were studied in HCV-negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0–inf was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, while the GS-331007 AUC0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose of sofosbuvir [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV-negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV-negative subjects with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). No clinically relevant differences in voxilaprevir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with once daily sofosbuvir/velpatasvir 400/100 mg for 12 weeks. The results were consistent with those observed in HCV negative subjects with ESRD requiring dialysis. The pharmacokinetics of voxilaprevir have not been studied in subjects with ESRD. However, voxilaprevir exposure following administration of VOSEVI is not expected to be meaningfully altered in HCV-infected subjects with ESRD requiring dialysis compared to subjects with normal renal function.

Patients with Hepatic Impairment:

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 was 126% and 143% higher in subjects with moderate and severe hepatic impairment, respectively, while the GS-331007 AUC0–24 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Velpatasvir plasma exposure (AUCinf) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetic analysis in HCV-infected subjects indicated that compensated cirrhosis (Child-Pugh A) had no clinically relevant effect on the exposure of velpatasvir.

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV-negative subjects with moderate and severe hepatic impairment (Child-Pugh B and C). Relative to subjects with normal hepatic function, the voxilaprevir AUCinf was 299% and 500% higher in subjects with moderate and severe hepatic impairment, respectively. Population pharmacokinetic analysis in HCV-infected subjects indicated that subjects with compensated cirrhosis (Child-Pugh A) had 73% higher exposure of voxilaprevir than those without cirrhosis [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

Race and Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that race and gender had no clinically relevant effect on the exposure of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.

Drug Interaction Studies

After oral administration of VOSEVI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.

Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed. Inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations without increasing GS-331007 plasma concentration. Coadministration with drugs that inhibit OATP may increase voxilaprevir plasma concentrations. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir and/or voxilaprevir.

Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, or OCT1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, or MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.

Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporters OCT1, renal transporters OCT2, OAT1, OAT3, or MATE1, or CYP or UGT1A1 enzymes.

The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, velpatasvir, and voxilaprevir are shown in Table 6. The effects of sofosbuvir, velpatasvir, voxilaprevir, sofosbuvir/velpatasvir, or VOSEVI on the exposure of coadministered drugs are shown in Table 7 [see Drug Interactions (7)].

No effect on the pharmacokinetic parameters of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir was observed with the combination of emtricitabine, rilpivirine, and tenofovir alafenamide; famotidine; gemfibrozil; or the combination of raltegravir, emtricitabine, and tenofovir DF.

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with VOSEVI (ethinyl estradiol/norgestimate) or its components sofosbuvir/velpatasvir (dolutegravir) or sofosbuvir (methadone).