Ledipasvir 90 mg, Sofosbuvir 400 mg Tablets

Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

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 ledipasvir and sofosbuvir tablets (90 mg/400 mg), 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) with food or without food. Ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) was 47 hours.