Absorption

The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose.

Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0–24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC0–24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects.

Effect of Food

Relative to fasting conditions, the administration of a single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0–inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food.

Distribution

Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 0.51 and 0.66.

Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.

Metabolism

In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces.

Sofosbuvir is extensively metabolized 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 catalyzed 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 biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. 

Elimination

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of HARVONI was 47 hours.

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of HARVONI were 0.5 and 27 hours, respectively.

Specific Populations

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

Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR12 >90%) were achieved in male and female subjects across the Phase 3 studies and the safety profiles are similar in females and males.

Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in 100 pediatric subjects 12 years of age and older infected with HCV genotype 1 receiving a daily dose of HARVONI (90 mg ledipasvir and 400 mg sofosbuvir). The pharmacokinetic properties of ledipasvir, sofosbuvir, and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 6. Exposures in pediatric subjects were similar to those observed in adults.

The pharmacokinetics of ledipasvir or sofosbuvir have not been established in pediatric patients less than 12 years of age [see Use in Specific Populations (8.4), and Clinical Studies (14.6)].

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5)].

Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe 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 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 (2.3) and Use in Specific Populations (8.6)].

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected subjects with severe renal impairment or ESRD requiring dialysis treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent with those observed in HCV-negative subjects with ESRD requiring dialysis.

Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0–inf) was similar in subjects with 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 ledipasvir [see Use in Specific Populations (8.7)]. 

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). 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) and Clinical Studies (14.5)]. 

Drug Interaction Studies

Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2.

Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by CYP or UGT1A1 enzymes are not expected.

The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table 7 [see Drug Interactions (7.2)].

No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with raltegravir and the combination of abacavir and lamivudine; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine, and tenofovir disoproxil fumarate. 

Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.

The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table 8 [see Drug Interactions (7)].

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.