Sofosbuvir and Velpatasvir (Page 5 of 11)

8.5 Geriatric Use

Clinical trials of sofosbuvir and velpatasvir included 156 subjects aged 65 and over (12% of total number of subjects in the Phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of sofosbuvir and velpatasvir is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.6), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

8.7 Hepatic Impairment

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Clinical and hepatic laboratory monitoring (including direct bilirubin), as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with sofosbuvir and velpatasvir and ribavirin [see Adverse Reactions (6.1)].

8.8 People Who Inject Drugs (PWID), Including Those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

Based on data from the Phase 2 trial SIMPLIFY, the safety and effectiveness of sofosbuvir and velpatasvir in subjects who self-reported injection drug use, including in those on concomitant MAT, were similar to the known safety and effectiveness profile of sofosbuvir and velpatasvir. No dosage adjustment of sofosbuvir and velpatasvir is recommended for PWID, including those on MAT for opioid use disorder [see Adverse Reactions (6.1) and Clinical Studies (14.7)].

10 OVERDOSAGE

No specific antidote is available for overdose with sofosbuvir and velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with sofosbuvir and velpatasvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir since velpatasvir is highly bound to plasma protein.

11 DESCRIPTION

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are fixed-dose combination tablets containing sofosbuvir and velpatasvir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor.

Each tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. The tablets include the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Sofosbuvir: The IUPAC name for sofosbuvir is (S)-isopropyl 2-((S)-(((2R ,3R ,4R ,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22 H29 FN3 O9 P and a molecular weight of 529.45. It has the following structural formula:

Chemical Structure
(click image for full-size original)

Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water.

Velpatasvir: The IUPAC name for velpatasvir is methyl {(1R)-2-[(2S ,4S)-2-(5-{2-[(2S ,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydro[2]benzopyrano[4′,3′:6,7]naphtho[1,2-d ]imidazol-9-yl}-1H -imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate. It has a molecular formula of C49 H54 N8 O8 and a molecular weight of 883.0. It has the following structural formula:

Chemical Structure
(click image for full-size original)

Velpatasvir is practically insoluble (less than 0.1 mg/mL) above pH 5, slightly soluble (3.6 mg/mL) at pH 2, and soluble (greater than 36 mg/mL) at pH 1.2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are a fixed-dose combination of sofosbuvir and velpatasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of sofosbuvir 400 mg (recommended dosage) and 1200 mg (3 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

The effect of velpatasvir 500 mg (5 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetic properties of sofosbuvir and velpatasvir are provided in Table 5. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, and velpatasvir are provided in Table 6.

Table 5 Pharmacokinetic Properties of Sofosbuvir and Velpatasvir
Sofosbuvir Velpatasvir
CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1.
*
Values refer to mean systemic exposure. Moderate meal = ~600 kcal, 30% fat; high fat meal = ~800 kcal, 50% fat. Sofosbuvir and velpatasvir can be taken with or without food.
GS-331007 is the primary circulating nucleoside metabolite of SOF.
t1/2 values refer to median terminal plasma half-life.
§
Single dose administration of [14 C] SOF or [14 C] VEL in mass balance studies.
Predominantly as GS-331007.
Absorption
Tmax (hr) 0.5–1 3
Effect of moderate meal (relative to fasting)* ↑ 60% ↑ 34%
Effect of high fat meal (relative to fasting)* ↑ 78% ↑ 21%
Distribution
% Bound to human plasma proteins 61–65 >99.5
Blood-to-plasma ratio 0.7 0.52–0.67
Metabolism
Metabolism Cathepsin ACES1HINT1 CYP2B6CYP2C8CYP3A4
Elimination
Major route of elimination SOF: metabolismGS-331007: glomerular filtration and active tubular secretion Biliary excretion as parent (77%)
t1/2 (hr) SOF: 0.5GS-331007: 25 15
% Of dose excreted in urine § 80 0.4
% Of dose excreted in feces § 14 94
Table 6 Multiple Dose Pharmacokinetic Parameters of Sofosbuvir and its Metabolite, GS-331007, and Velpatasvir Following Oral Administration of Sofosbuvir and Velpatasvir in HCV-Infected Adults
ParameterMean (%CV) Sofosbuvir * GS-331007 Velpatasvir
CV = coefficient of variation; NA = not applicable.
*
From Population PK analysis, N = 666
From Population PK analysis, N = 1029
From Population PK analysis, N = 1025
Cmax (ng/mL) 567 (30.7) 898 (26.7) 259 (54.3)
AUCtau (ng∙hr/mL) 1268 (38.5) 14372 (28.0) 2980 (51.3)
Ctrough (ng/mL) NA 42 (67.3)

Sofosbuvir and GS-331007 AUC0–24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=331), velpatasvir AUC0–24 and Cmax were 37% lower and 42% lower, respectively, in HCV-infected subjects.

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 more than or near dose-proportional increase in exposures 25 mg to 150 mg in HCV-infected patients when coadministered with sofosbuvir. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg.

Specific Populations

Pediatric Patients: The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were determined in HCV genotype 1, 2, 3, 4, or 6 infected pediatric subjects 3 years of age and older receiving a daily dose of sofosbuvir and velpatasvir as described below in Table 7. Sofosbuvir AUCtau and Cmax and velpatasvir Cmax values were 67%, 69%, and 78% higher in pediatric subjects ≥30 kg, 68%, 70%, and 96% higher in pediatric subjects 17 to <30 kg, and 103%, 135%, and 92% higher in pediatric subjects <17 kg compared to those observed in adults. These differences were not considered clinically significant. GS-331007 exposures and velpatasvir AUCtau and Ctau values in pediatric subjects were similar to those observed in adults.

Table 7 Exposures of Sofosbuvir, GS-331007, and Velpatasvir at Steady-State in HCV-Infected Pediatric Subjects 3 Years of Age and Older *
Weight Group Dose PK Parameter Mean (%CV)
Sofosbuvir GS-331007 Velpatasvir
CV = coefficient of variation; NA = not applicable.
*
Population PK derived parameters
Sofosbuvir N=11; GS-331007 N=11; Velpatasvir N=11
Sofosbuvir N=62; GS-331007 N=64; Velpatasvir N=64
§
Sofosbuvir N=90; GS-331007 N=101; Velpatasvir N=101
<17 kg 150/37.5 mg Cmax (ng/mL) 1550 (65.2) 1090 (17.0) 488 (46.6)
AUCtau (ng∙hr/mL) 2830 (63.7) 11900 (19.7) 4480 (53.4)
Ctrough (ng/mL) NA 57.4 (82.7)
17 to <30 kg 200/50 mg Cmax (ng/mL) 1200 (73.8) 1070 (27.2) 483 (39.5)
AUCtau (ng∙hr/mL) 2280 (55.6) 11400 (43.3) 4090 (38.5)
Ctrough (ng/mL) NA 43 (65.8)
≥30 kg § 400/100 mg Cmax (ng/mL) 1310 (91.4) 1180 (24.6) 456 (56.4)
AUCtau (ng∙hr/mL) 2570 (82.8) 13600 (27.6) 4240 (46.7)
Ctrough (ng/mL) NA 42.2 (66.4)

The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir have not been established in pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and Clinical Studies (14.7)].

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 82 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir [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 [see Dosage and Administration (2.6) 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 [see Use in Specific Populations (8.6)].

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks. The results were generally consistent with those in HCV negative subjects with ESRD requiring dialysis.

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 Class B and C, respectively). Relative to subjects with normal hepatic function, the sofosbuvir AUC0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7)].

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 Class 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 pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of velpatasvir [see Use in Specific Populations (8.7)].

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

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

Drug Interaction Studies

After oral administration of sofosbuvir and velpatasvir, 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 and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also transported by OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of sofosbuvir and velpatasvir [see Warnings and Precautions (5.3) and Drug Interactions (7.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir and/or velpatasvir plasma concentrations without increasing GS-331007 plasma concentration. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir.

Velpatasvir is an inhibitor of drug transporter 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 concentration, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3, or MATE1, or CYP or UGT1A1 enzymes.

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

The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, and velpatasvir are shown in Table 8. The effects of sofosbuvir, velpatasvir, or sofosbuvir and velpatasvir on the exposure of coadministered drugs are shown in Table 9 [see Drug Interactions (7)].

Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir, GS-331007, and Velpatasvir in the Presence of the Coadministered Drug *
Coadministered Drug Dose of Coadministered Drug(mg) SOF Dose(mg) VEL Dose(mg) N Mean Ratio (90% CI) of Sofosbuvir, GS-331007, and Velpatasvir PK With/Without Coadministered DrugNo Effect=1.00
Cmax AUC Cmin
NA = not available/not applicable, ND = not dosed, DF = disoproxil fumarate.
*
All interaction studies conducted in healthy volunteers.
Administered as Atripla® (efavirenz, emtricitabine, and tenofovir DF fixed-dose combination).
Administered as Genvoya® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fixed-dose combination).
§
Administered as Stribild® (elvitegravir, cobicistat, emtricitabine, and tenofovir DF fixed-dose combination).
Sofosbuvir and velpatasvir tablets were administered under fasted conditions in the reference arms.
Atazanavir/ ritonavir + emtricitabine/ tenofovir DF 300/100 + 200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 1.12(0.97, 1.29) 1.22(1.12, 1.33) NA
GS-331007 1.21(1.12, 1.29) 1.32(1.27, 1.36) 1.42(1.37, 1.49)
velpatasvir 1.55(1.41, 1.71) 2.42(2.23, 2.64) 4.01(3.57, 4.50)
Carbamazepine 300 twice daily 400 single dose ND 24 sofosbuvir 0.52(0.43, 0.62) 0.52(0.46, 0.59) NA
GS-331007 1.04(0.97, 1.11) 0.99(0.94, 1.04) NA
Cyclosporine 600 single dose 400 single dose ND 19 sofosbuvir 2.54(1.87, 3.45) 4.53(3.26, 6.30) NA
GS-331007 0.60(0.53, 0.69) 1.04(0.90, 1.20) NA
ND 100 single dose 12 velpatasvir 1.56(1.22, 2.01) 2.03(1.51, 2.71) NA
Darunavir/ ritonavir + emtricitabine/ tenofovir DF 800/100 + 200/300 once daily 400 once daily 100 once daily 29 sofosbuvir 0.62(0.54, 0.71) 0.72(0.66, 0.80) NA
GS-331007 1.04(0.99, 1.08) 1.13(1.08, 1.18) 1.13(1.06, 1.19)
velpatasvir 0.76(0.65, 0.89) 0.84(0.72, 0.98) 1.01(0.87, 1.18)
Efavirenz/ emtricitabine/ tenofovir DF 600/200/300 once daily 400 once daily 100 once daily 14 sofosbuvir 1.38(1.14, 1.67) 0.97(0.83, 1.14) NA
GS-331007 0.86(0.80, 0.93) 0.90(0.85, 0.96) 1.01(0.95, 1.07)
velpatasvir 0.53(0.43, 0.64) 0.47(0.39, 0.57) 0.43(0.36, 0.52)
Elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide 150/150/200/10 once daily 400 once daily 100 once daily 24 sofosbuvir 1.23(1.07, 1.42) 1.37(1.24, 1.52) NA
GS-331007 1.29(1.25, 1.33) 1.48(1.43, 1.53) 1.58(1.52, 1.65)
velpatasvir 1.30(1.17, 1.45) 1.50(1.35, 1.66) 1.60(1.44, 1.78)
Elvitegravir/ cobicistat/emtricitabine/tenofovir DF § 150/150/200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 1.01(0.85, 1.19) 1.24(1.13, 1.37) NA
GS-331007 1.13(1.07, 1.18) 1.35(1.30, 1.40) 1.45(1.38, 1.52)
velpatasvir 1.05(0.93, 1.19) 1.19(1.07, 1.34) 1.37(1.22, 1.54)
Famotidine 40 single dose simultaneously with sofosbuvir and velpatasvir tablets 400 single dose 100 single dose 60 sofosbuvir 0.92(0.82, 1.05) 0.82(0.74, 0.91) NA
GS-331007 0.84(0.78, 0.89) 0.94(0.91, 0.98) NA
velpatasvir 0.80(0.70, 0.91) 0.81(0.71, 0.91) NA
40 single dose 12 hours prior to sofosbuvir and velpatasvir tablets 60 sofosbuvir 0.77(0.68, 0.87) 0.80(0.73, 0.88) NA
GS-331007 1.20(1.13, 1.28) 1.04(1.01, 1.08) NA
velpatasvir 0.87(0.76, 1.00) 0.85(0.74, 0.97) NA
Ketoconazole 200 twice daily ND 100 single dose 12 velpatasvir 1.29(1.02, 1.64) 1.71(1.35, 2.18) NA
Lopinavir/ ritonavir + emtricitabine/ tenofovir DF 4×200/50 + 200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 0.59(0.49, 0.71) 0.71(0.64, 0.78) NA
GS-331007 1.01(0.98, 1.05) 1.15(1.09, 1.21) 1.15(1.07, 1.25)
velpatasvir 0.70(0.59, 0.83) 1.02(0.89, 1.17) 1.63(1.43, 1.85)
Methadone 30 to 130 daily 400 once daily ND 14 sofosbuvir 0.95(0.68, 1.33) 1.30(1.00, 1.69) NA
GS-331007 0.73(0.65, 0.83) 1.04(0.89, 1.22) NA
Omeprazole 20 once daily simultaneously with sofosbuvir and velpatasvir tablets 400 single dose fasted 100 single dose fasted 60 sofosbuvir 0.66(0.55, 0.78) 0.71(0.60, 0.83) NA
GS-331007 1.18(1.10, 1.26) 1.00(0.95, 1.05) NA
velpatasvir 0.63(0.50, 0.78) 0.64(0.52, 0.79) NA
20 once daily 12 hours prior to sofosbuvir and velpatasvir tablets 400 single dose fasted 100 single dose fasted 60 sofosbuvir 0.55(0.47, 0.64) 0.56(0.49, 0.65) NA
GS-331007 1.26(1.18, 1.34) 0.97(0.94, 1.01) NA
velpatasvir 0.43(0.35, 0.54) 0.45(0.37, 0.55) NA
20 once daily 2 hours prior to sofosbuvir and velpatasvir tablets 400 single dose fed 100 single dose fed 40 sofosbuvir 0.84(0.68, 1.03) 1.08(0.94, 1.25) NA
GS-331007 0.94(0.88, 1.02) 0.99(0.96, 1.03) NA
velpatasvir 0.52(0.43, 0.64) 0.62(0.51, 0.75) NA
20 once daily 4 hours after sofosbuvir and velpatasvir tablets 400 single dose fed 100 single dose fed 38 sofosbuvir 0.79(0.68, 0.92) 1.05(0.94, 1.16) NA
GS-331007 0.91(0.85, 0.98) 0.99(0.95, 1.02) NA
velpatasvir 0.67(0.58, 0.78) 0.74(0.63, 0.86) NA
40 once daily 4 hours after sofosbuvir and velpatasvir tablets 400 single dose fed 100 single dose fed 40 sofosbuvir 0.70(0.57, 0.87) 0.91(0.76, 1.08) NA
GS-331007 1.01(0.96, 1.07) 0.99(0.94, 1.03) NA
velpatasvir 0.44(0.34, 0.57) 0.47(0.37, 0.60) NA
Rifabutin 300 once daily 400 single dose ND 20 sofosbuvir 0.64(0.53, 0.77) 0.76(0.63, 0.91) NA
GS-331007 1.15(1.03, 1.27) 1.03(0.95, 1.12) NA
Rifampin 600 once daily 400 single dose ND 17 sofosbuvir 0.23(0.19, 0.29) 0.28(0.24, 0.32) NA
GS-331007 1.23(1.14, 1.34) 0.95(0.88, 1.03) NA
ND 100 single dose 12 velpatasvir 0.29(0.23, 0.37) 0.18(0.15, 0.22) NA
600 single dose ND 100 single dose 12 velpatasvir 1.28(1.05, 1.56) 1.46(1.17, 1.83) NA
Tacrolimus 5 single dose 400 single dose ND 16 sofosbuvir 0.97(0.65, 1.43) 1.13(0.81, 1.57) NA
GS-331007 0.97(0.83, 1.14) 1.00(0.87, 1.13) NA

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

Table 9 Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir, Velpatasvir, or Sofosbuvir and Velpatasvir *
Coadministered Drug Dose of Coadministered Drug (mg) SOF Dose (mg) VEL Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Sofosbuvir, Velpatasvir, or Sofosbuvir and VelpatasvirNo Effect=1.00
Cmax AUC Cmin
NA = not available/not applicable, ND = not dosed, DF = disoproxil fumarate.
*
All interaction studies conducted in healthy volunteers.
Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF.
Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF.
§
Administered as Atripla (efavirenz, emtricitabine, and tenofovir DF fixed-dose combination).
Administered as Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fixed-dose combination).
#
Administered as Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir DF fixed-dose combination).
Þ
Administered as Complera® (emtricitabine, rilpivirine, and tenofovir DF fixed-dose combination).
Atazanavir/ ritonavir + emtricitabine/ tenofovir DF atazanavir 300 once daily 400 once daily 100 once daily 24 1.09(1.00, 1.19) 1.20(1.10, 1.31) 1.39(1.20, 1.61)
ritonavir 100 once daily 0.89(0.82, 0.97) 0.97(0.89, 1.05) 1.29(1.15, 1.44)
emtricitabine 200 once daily 1.01(0.96, 1.06) 1.02(0.99, 1.04) 1.06(1.02, 1.11)
tenofovir DF 300 once daily 1.55(1.43, 1.68) 1.30(1.24, 1.36) 1.39(1.31, 1.48)
Atorvastatin 40 single dose 400once daily 100once daily 26 1.68(1.49, 1.89) 1.54(1.45, 1.64) NA
Darunavir/ ritonavir + emtricitabine/ tenofovir DF darunavir 800 once daily 400 once daily 100 once daily 29 0.90(0.86, 0.95) 0.92(0.87, 0.98) 0.87(0.79, 0.95)
ritonavir 100 once daily 1.07(0.97, 1.17) 1.12(1.05, 1.19) 1.09(1.02, 1.15)
emtricitabine 200 once daily 1.05(1.01, 1.08) 1.05(1.02, 1.08) 1.04(0.98, 1.09)
tenofovir DF 300 once daily 1.55(1.45, 1.66) 1.39(1.33, 1.44) 1.52(1.45, 1.59)
Digoxin 0.25 single dose ND 100 21 1.88(1.71, 2.08) 1.34(1.13, 1.60) NA
Efavirenz/ emtricitabine/ tenofovir DF § efavirenz 600 once daily 400 once daily 100 once daily 15 0.81(0.74, 0.89) 0.85(0.80, 0.91) 0.90(0.85, 0.95)
emtricitabine 200 once daily 1.07(0.98, 1.18) 1.07(1.00, 1.14) 1.10(0.97, 1.25)
tenofovir DF 300 once daily 1.77(1.53, 2.04) 1.81(1.68, 1.94) 2.21(2.00, 2.43)
Elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide elvitegravir 150 once daily 400 once daily 100 once daily 24 0.87(0.80, 0.94) 0.94(0.88, 1.00) 1.08(0.97, 1.20)
cobicistat 150 once daily 1.16(1.09, 1.23) 1.30(1.23, 1.38) 2.03(1.67, 2.48)
emtricitabine 200 once daily 1.02(0.97, 1.06) 1.01(0.98, 1.04) 1.02(0.97, 1.07)
tenofovir alafenamide 10 once daily 0.80(0.68, 0.94) 0.87(0.81, 0.94) NA
Elvitegravir/ cobicistat/emtricitabine/tenofovir DF # elvitegravir 150 once daily 400 once daily 100 once daily 24 0.93(0.86, 1.00) 0.93(0.87, 0.99) 0.97(0.91, 1.04)
cobicistat 150 once daily 1.11(1.06, 1.17) 1.23(1.17, 1.29) 1.71(1.54, 1.90)
emtricitabine 200 once daily 1.02(0.97, 1.08) 1.01(0.98, 1.04) 1.06(1.01, 1.11)
tenofovir DF 300 once daily 1.36(1.25, 1.47) 1.35(1.29, 1.42) 1.45(1.39, 1.51)
Emtricitabine/ rilpivirine/ tenofovir DF Þ emtricitabine 200 once daily 400 once daily 100 once daily 24 0.95(0.90, 1.00) 0.99(0.97, 1.02) 1.05(0.99, 1.11)
rilpivirine 25 once daily 0.93(0.88, 0.98) 0.95(0.90, 1.00) 0.96(0.90, 1.03)
tenofovir DF 300 once daily 1.44(1.33, 1.55) 1.40(1.34, 1.46) 1.84(1.76, 1.92)
Norelgestromin norgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily ND 100 once daily 13 0.97(0.88, 1.07) 0.90(0.82, 0.98) 0.92(0.83, 1.03)
400 once daily ND 15 1.07(0.94, 1.22) 1.06(0.92, 1.21) 1.07(0.89, 1.28)
Norgestrel ND 100 once daily 13 0.96(0.78, 1.19) 0.91(0.73, 1.15) 0.92(0.73, 1.18)
400 once daily ND 15 1.18(0.99, 1.41) 1.19(0.98, 1.45) 1.23(1.00, 1.51)
Ethinyl estradiol ND 100 once daily 12 1.39(1.17, 1.66) 1.04(0.87, 1.24) 0.83(0.65, 1.06)
400 once daily ND 15 1.15(0.97, 1.36) 1.09(0.94, 1.26) 0.99(0.80, 1.23)
Pravastatin 40 single dose ND 100 once daily 18 1.28(1.08, 1.52) 1.35(1.18, 1.54) NA
Rosuvastatin 10 single dose ND 100 once daily 18 2.61(2.32, 2.92) 2.69(2.46, 2.94) NA
Raltegravir + emtricitabine/ tenofovir DF emtricitabine 200 once daily 400 once daily 100 once daily 30 1.08(1.04, 1.12) 1.05(1.03, 1.07) 1.02(0.97, 1.08)
tenofovir DF 300 once daily 1.46(1.39, 1.54) 1.40(1.34, 1.45) 1.70(1.61, 1.79)
raltegravir 400 twice daily 1.03(0.74, 1.43) 0.97(0.73, 1.28) 0.79(0.42, 1.48)
Tacrolimus 5 single dose 400 single dose ND 16 0.73(0.59, 0.90) 1.09(0.84, 1.40) NA

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed or is expected with sofosbuvir and velpatasvir (buprenorphine/naloxone, dolutegravir, lopinavir/ritonavir, or methadone) or its components sofosbuvir (cyclosporine) or velpatasvir (cyclosporine).

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