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Pharmacology: Pharmacodynamics: Mechanism of action: Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.
Antiviral activity: The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length or chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in Table 1. The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in Table 2. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageThe presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of velpatasvir by 13-fold against genotype 1a HCV replicons.
Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
Resistance: In cell culture: HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, the ability of the active triphosphate of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution was reduced compared to its ability to inhibit wild-type recombinant NS5B polymerase, as indicated by a 8.5- to 24-fold increase in the 50% inhibitory concentration (IC50).
In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cell culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a and 6a. Variants were selected at NS5A resistance associated positions 24, 28, 30, 31, 32, 58, 92 and 93. The resistance associated variants (RAVs) selected in 2 or more genotypes were F28S, L31I/V and Y93H. Site-directed mutagenesis of known NS5A RAVs showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility. Combinations of these variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone.
In clinical studies Studies in patients without cirrhosis and patients with compensated cirrhosis: In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) qualified for resistance analysis due to virologic failure. One additional patient with genotype 3 HCV infection at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the virological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure.
Of the 2 genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93N and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure. Both patients had virus at baseline harboring NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed at failure in the 2 patients.
Of the 10 genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No NS5B NI RAVs were observed at failure in the 10 patients.
Studies in patients with decompensated cirrhosis: In one Phase 3 study in patients with decompensated cirrhosis who received Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV for 12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due to virologic failure. No patients with genotype 2 or 4 HCV infection in the Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV 12 weeks group experienced virologic failure.
The 1 virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure.
Of the 2 genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Another patient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data from this patient was consistent with non-adherence to treatment.
In this study, 2 patients treated with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 or 24 weeks without ribavirin had emergent NS5B S282T at low levels (< 5%) along with L159F.
Effect of baseline HCV resistance-associated variants on treatment outcome: Studies in patients without cirrhosis and patients with compensated cirrhosis: Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients without cirrhosis or with compensated cirrhosis in three Phase 3 clinical studies (ASTRAL-1, ASTRAL-2 and ASTRAL-3). Of the 1,035 patients treated with sofosbuvir/velpatasvir in the three Phase 3 clinical studies, 1,023 patients were included in the analysis of NS5A RAVs; 7 patients were excluded as they neither achieved sustained virologic response (SVR12) nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencing failed. In the pooled analysis of the Phase 3 studies, 380/1,023 (37%) patients' virus had baseline NS5A RAVs. Genotype 2, 4, and 6 HCV-infected patients had a higher prevalence of NS5A RAVs (70%, 63% and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%) HCV-infected patients.
Baseline RAVs had no relevant impact on SVR12 rates in patients infected with genotype 1, 2, 4, 5 and 6 HCV, as summarised in Table 3. Genotype 3 infected patients with the NS5A RAV Y93H at baseline had a lower SVR12 rate than patients without Y93H after treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks, as summarised in Table 4. In the ASTRAL-3 study, the Y93H RAV was detected at baseline in 9% of patients treated with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg. (See Tables 3 and 4.)
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Click on icon to see table/diagram/imageThe NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 studies. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I.
Studies in patients with decompensated cirrhosis (CPT Class B): Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients with decompensated cirrhosis in one Phase 3 study (ASTRAL-4). Of the 87 patients treated with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV, 85 patients were included in the analysis of NS5A RAVs; 2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among the patients who received treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV for 12 weeks, 29% (25/85) of patients had baseline virus with NS5A RAVs: 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with genotype 1, 2, 3 and 4 HCV, respectively.
SVR12 in patients with or without baseline NS5A RAVs in the Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV 12 week group for this study is shown in Table 5. (See Table 5.)
Click on icon to see table/diagram/imageThe single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5A substitution Y93H at baseline; pharmacokinetic data from this patient was consistent with non-adherence to treatment.
Three patients in the Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV 12 week group had baseline NS5B NI RAVs (N142T and L159F) and all three patients achieved SVR12.
Cross-resistance: In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir and daclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all velpatasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of direct acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg has not been assessed in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.
Clinical efficacy and safety: The efficacy of Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg was evaluated in three Phase 3 studies in patients with genotype 1 to 6 HCV infection with or without compensated cirrhosis one Phase 3 study in patients with genotype 1 to 6 HCV infection with decompensated cirrhosis, and one Phase 3 study in HCV/HIV-1 co-infected patients with genotype 1 to 6 HCV infection, as summarised in Table 6. (See Table 6.)
Click on icon to see table/diagram/imageThe ribavirin dose was weight-based (1,000 mg daily administered in two divided doses for patients < 75 kg and 1,200 mg for those ≥ 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 studies or in combination with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg in the ASTRAL-4 study. Ribavirin dose adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical studies using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate.
Clinical studies in patients without cirrhosis and patients with compensated cirrhosis Genotype 1, 2, 4, 5 and 6 HCV-infected adults - ASTRAL-1 (study 1138): ASTRAL-1 was a randomised, double-blind, placebo-controlled study that evaluated 12 weeks of treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg compared with 12 weeks of placebo in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Patients with genotype 1, 2, 4 or 6 HCV infection were randomised in a 5:1 ratio to treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV infection were enrolled to the Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg group. Randomisation was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis.
Demographics and baseline characteristics were balanced between the Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg and placebo group. Of the 740 treated patients, the median age was 56 years (range: 18 to 82); 60% of the patients were male; 79% were White, 9% were Black; 21% had a baseline body mass index of at least 30 kg/m2; the proportions of patients with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5% and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.
Table 7 presents the SVR12 for the ASTRAL-1 study by HCV genotypes. No patients in the placebo group achieved SVR12. (See Table 7.)
Click on icon to see table/diagram/imageGenotype 2 HCV-infected adults - ASTRAL-2 (study 1139): ASTRAL-2 was a randomised, open-label study that evaluated 12 weeks of treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg compared with 12 weeks of treatment with SOF+RBV in patients with genotype 2 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks or SOF+RBV for 12 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced).
Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated patients, the median age was 58 years (range: 23 to 81); 59% of the patients were male; 88% were White, 7% were Black; 33% had a baseline body mass index of at least 30 kg/m2; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels of at least 800,000 IU/mL; 14% had compensated cirrhosis and 15% were treatment-experienced.
Table 8 presents the SVR12 for the ASTRAL-2 study. (See Table 8.)
Click on icon to see table/diagram/imageTreatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks demonstrated the statistical superiority (p = 0.018) over treatment with SOF+RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%).
Genotype 3 HCV-infected adults - ASTRAL-3 (study 1140): ASTRAL-3 was a randomised, open-label study that evaluated 12 weeks of treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg compared with 24 weeks of treatment with SOF+RBV in patients with genotype 3 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks or SOF+RBV for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced).
Demographics and baseline characteristics were balanced across the two treatment groups. Of the 552 treated patients, the median age was 52 years (range: 19 to 76); 62% of the patients were male; 89% were White, 9% were Asian; 1% were Black; 20% had a baseline body mass index of at least 30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels of at least 800,000 IU/mL, 30% had compensated cirrhosis and 26% were treatment-experienced.
Table 9 presents the SVR12 for the ASTRAL-3 study. (See Table 9.)
Click on icon to see table/diagram/imageTreatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks demonstrated the statistical superiority (p < 0.001) compared to treatment with SOF+RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%).
SVR12 for selected subgroups are presented in Table 10. (See Table 10.)
Click on icon to see table/diagram/imageClinical studies in patients with decompensated cirrhosis- ASTRAL-4 (study 1137): ASTRAL-4 was a randomised, open-label study in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and CPT Class B cirrhosis. Patients were randomised in a 1:1:1 ratio to treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 12 weeks, Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg + RBV for 12 weeks or Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg for 24 weeks. Randomisation was stratified by HCV genotype (1, 2, 3, 4, 5, 6 and indeterminate).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated patients, the median age was 59 years (range: 40 to 73); 70% of the patients were male; 90% were White, 6% were Black; 42% had a baseline body mass index of at least 30 kg/m2. The proportions of patients with genotype 1, 2, 3, 4 or 6 HCV were 78%, 4%, 15%, 3%, and < 1% (1 patient), respectively. No patients with genotype 5 HCV infection were enrolled. 76% of the patients had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels of at least 800,000 IU/mL, 55% were treatment-experienced; 90% and 95% of patients had CPT Class B cirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively.
Table 11 presents the SVR12 for the ASTRAL-4 study by HCV genotype. (See Table 11.)
Click on icon to see table/diagram/imageTable 12 presents the virologic outcome for patients with genotype 1 or 3 HCV infection in the ASTRAL-4 study.
No patients with genotype 2, 4 or 6 HCV infection experienced virologic failure. (See Table 12.)
Click on icon to see table/diagram/imageChanges in the parameters found in the CPT score system in patients achieving SVR12 in ASTRAL-4 (all 3 regimens) are shown in Table 13. (See Table 13.)
Click on icon to see table/diagram/imageClinical studies in patients with HCV/HIV-1 Co-infection - ASTRAL-5 (study 1202): ASTRAL-5 evaluated 12 weeks of treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg in patients with genotype 1, 2, 3, or 4 HCV infection who were co-infected with HIV-1 (HCV genotype 5 and 6 allowed, but no such patients were included). Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with a ritonavir boosted protease inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir or emtricitabine/tenofovir disoproxil fumarate /elvitegravir/cobicistat.
Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients were male; 51% were white; 45% were black; 22% had a baseline body mass index ≥ 30 kg/m2; 19 patients (18%) had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/μL (range: 183-1513 cells/μL).
Table 14 presents the SVR12 for the ASTRAL-5 study by HCV genotype. (See Table 14.)
Click on icon to see table/diagram/imageSVR12 was achieved by 19/19 patients with cirrhosis. No patient had HIV-1 rebound during the study, and CD4+ counts were stable during treatment.
Clinical studies in patients with Renal Impairment - study 4062: Study 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg in 59 HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7% ,3%, and 9%, respectively. At baseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidney transplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the three patients that did not achieve SVR12, one had completed Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg treatment and relapsed and two did not meet virologic failure criteria.
Elderly: Clinical studies of Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg included 156 patients aged 65 and over (12% of total number of patients in the Phase 3 clinical studies). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups.
Pharmacokinetics: Absorption: Following oral administration of Sofosbuvir and Velpatasvir tablet, sofosbuvir was absorbed quickly within 1-hour post-dose. The predominant circulating metabolite of sofosbuvir GS-331007 reached its maximum absorption at 3 hours post-dose. Velpatasvir absorbed at 3 hours post-dose.
Effects of food: Sofosbuvir and Velpatasvir tablet can be administered without regard to food.
Distribution: Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL.
Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 μg/mL to 1.8 μg/mL.
Biotransformation: Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosysthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total systemic exposure.
Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug.
The monohydroxylated and desmethylated velpatasvir were the metabolites identified in human plasma. Unchanged velpatasvir is the major species present in faeces.
Elimination: The renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Sofosbuvir and Velpatasvir tablet were 0.5 and 25 hours, respectively.
The biliary excretion of parent drug was a major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of Sofosbuvir and Velpatasvir tablet was approximately 15 hours.
Linearity/non-linearity: Velpatasvir AUC increases in a nearly dose proportional manner over the dose range of 25 mg to 150 mg. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1,200 mg.
In vitro potential for Sofosbuvir and Velpatasvir drug-drug interations: Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also a substrate of OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.
Velpatasvir is an inhibitor of drug transporter 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 plasma concentration, velpatasvir is not an inhibitor of hepatic transporters bile salt export pump (BSEP), sodium taurocholate cotransporter protein (NTCP), OATP2B1, OATP1A2 or organic cation transporter (OCT) 1, renal transporters OCT2, OAT1, OAT3, multidrug resistance-associated protein 2 (MRP2) or multidrug and toxin extrusion protein (MATE) 1, or CYP or uridine glucuronosyltransferase (UGT) 1A1 enzymes.
Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Pharmacokinetics in special populations: Race and gender: No clinically relevant pharmacokinetic differences due to race or gender have been identified for sofosbuvir, GS-331007 or velpatasvir.
Elderly: Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir.
Renal impairment: A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Sofosbuvir and Velpatasvir Film Coated Tablets 400 mg/100 mg compared to subjects with normal renal function, as described in the text as follows, are provided in Table 15. (See Table 15.)
Click on icon to see table/diagram/imageThe pharmacokinetics of sofosbuvir was studied in HCV negative patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir relative, to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered dose.
In HCV-infected patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment.
The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).
The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected patients with ESRD requiring dialysis treated with Sofosbuvir and Velpatasvir tablet (n=59) for 12 weeks and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials.
Hepatic impairment: Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was higher. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007.
The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV negative patients with moderate and severe hepatic impairment (Child-Pugh-Turcotte (CPT) Class B and C). Compared to subjects with normal hepatic function velpatasvir total plasma exposure (AUCinf) was similar in patients with moderate or severe hepatic impairment. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to velpatasvir (see Posology under Dosage & Administration).
Body weight: Body weight did not have a clinically significant effect on sofosbuvir or velpatasvir exposure according to a population pharmacokinetic analysis.
Paediatric population: The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir in paediatric patients have not been established (see Posology under Dosage & Administration).
