Actions of Ledipasvir and sofosbuvir in details
Pharmacology: Pharmacodynamics: Mechanism of Action: Ledipasvir and sofosbuvir is a fixed-dose combination of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) which are direct-acting antiviral agents against the hepatitis C virus (HCV).
Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) targets NS5A as its mode of action.
Sofosbuvir (Ledipasvir and sofosbuvir) is an inhibitor of the HCV NS5B ribonucleic acid (RNA)-dependent RNA polymerase, which is required for viral replication. Sofosbuvir (Ledipasvir and sofosbuvir) is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with median inhibitory concentration (IC50) values ranging from 0.7-2.6 microM. GS-461203 is neither an inhibitor of human deoxyribonucleic acid (DNA) and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Cardiac Electrophysiology: Thorough QT studies have been conducted for Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir).
The effect of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3 period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) does not prolong QTc interval to any clinically relevant extent.
The effect of Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg (maximum recommended dosage) and 1,200 mg (3 times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 4 period crossover thorough QT trial in 59 healthy subjects. At a dose 3 times the maximum recommended dose, Sofosbuvir (Ledipasvir and sofosbuvir) does not prolong QTc to any clinically relevant extent.
Clinical Studies: Overview of Clinical Trials: The efficacy of Ledipasvir and sofosbuvir was evaluated in three phase 3 trials of 1,518 subjects with genotype 1 chronic hepatitis C (CHC) with compensated liver disease: Study ION-3: Non-cirrhotic treatment-naive subjects; Study ION-1: Cirrhotic and non-cirrhotic treatment-naive subjects; and Study ION-2: Cirrhotic and non-cirrhotic subjects who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor.
All three phase 3 trials evaluated efficacy of Ledipasvir and sofosbuvir (1 fixed-dose tablet of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 90 mg and of Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg administered once daily) with or without ribavirin. Treatment duration was fixed in each trial. Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL.
Sustained virologic response (SVR) was the primary endpoint and was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
Clinical Trials in Treatment-Naive Subjects: Treatment-Naive Adults without Cirrhosis-ION-3 (Study 0108): ION-3 was a randomized, open-label trial in treatment-naive non-cirrhotic subjects with genotype 1 CHC. Subjects were randomized in a 1:1:1 ratio to one of the following 3 treatment groups and stratified by HCV genotype (1a vs 1b): Ledipasvir and sofosbuvir for 8 weeks, Ledipasvir and sofosbuvir for 12 weeks or Ledipasvir and sofosbuvir plus ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20-75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18-56 kg/m2); 81% had baseline HCV RNA levels ≥800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).
Table 1 presents the response rates for the Ledipasvir and sofosbuvir treatment groups in the ION-3 trial after 8 and 12 weeks of Ledipasvir and sofosbuvir treatment. Ribavirin was not shown to increase the response rates observed with Ledipasvir and sofosbuvir. Therefore, the Ledipasvir and sofosbuvir plus ribavirin arm is not presented in Table 1.
The treatment difference between the 8-week and 12-week treatment of Ledipasvir and sofosbuvir was -2.3% (97.5% confidence interval -7.2% to 2.5%). Among subjects with a baseline HCV RNA <6 million IU/mL, the SVR was 97% (119/123) with 8-week treatment and 96% (126/131) with 12-week treatment of Ledipasvir and sofosbuvir.
Treatment-Naive Adults with or without Cirrhosis-ION-1 (Study 0102): ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with Ledipasvir and sofosbuvir with or without ribavirin in 865 treatment-naive subjects with genotype 1 CHC including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive Ledipasvir and sofosbuvir for 12 weeks, Ledipasvir and sofosbuvir plus ribavirin for 12 weeks, Ledipasvir and sofosbuvir for 24 weeks or Ledipasvir and sofosbuvir plus ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a versus 1b). The interim primary endpoint analysis for SVR included all subjects enrolled in the 12-week treatment groups (N=431). Sustained virologic response (SVR) rates for all subjects enrolled in the 24-week treatment groups (N=434) were not available at the time of interim analysis.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18-80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18-48 kg/m2); 79% had baseline HCV RNA levels ≥800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 3 presents the response rates for the treatment group of Ledipasvir and sofosbuvir for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase response rates observed with Ledipasvir and sofosbuvir. Therefore, the Ledipasvir and sofosbuvir plus ribavirin arm is not presented in Table 3.
Response rates for selected subgroups are presented in Table 4.
Clinical Trials in Subjects Who Failed Prior Therapy: Previously-Treated Adults with or without Cirrhosis-ION-2 (Study 0109): ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with Ledipasvir and sofosbuvir with or without ribavirin in genotype 1 HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive Ledipasvir and sofosbuvir for 12 weeks, Ledipasvir and sofosbuvir plus ribavirin for 12 weeks, Ledipasvir and sofosbuvir for 24 weeks or Ledipasvir and sofosbuvir plus ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24-75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19-50 kg/m2); 89% had baseline HCV RNA levels ≥800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis.
Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were nonresponder. Fifty-three percent (53%) of the subjects failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were nonresponder.
Table 5 presents the response rates for the Ledipasvir and sofosbuvir treatment groups in the ION-2 trial. Ribavirin was not shown to increase response rates observed with Ledipasvir and sofosbuvir. Therefore, the Ledipasvir and sofosbuvir plus ribavirin arms are not presented in Table 5.
Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24.
Response rates and relapse rates for selected subgroups are presented in Tables 6 and 7.
Pharmacokinetics: Absorption: The pharmacokinetic properties of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and 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, Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) median peak concentrations were observed 4-4.5 hrs post-dose. Sofosbuvir (Ledipasvir and sofosbuvir) was absorbed quickly and the peak median plasma concentration was observed 0.8-1 hr post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5-4 hrs post-dose.
Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state area under the concentration time-curve (AUC0-24) for Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) (N=2,113), Sofosbuvir (Ledipasvir and sofosbuvir) (N=1,542) and GS-331007 (N=2,113) were 7,290, 1,320 and 12,000 ng·hr/mL, respectively. Steady-state peak plasma concentration (Cmax) for Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir (Ledipasvir and 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 with a moderate fat (approximately 600 kCal, 25-30% fat) or high fat (approximately 1,000 kCal, 50% fat) meal increased Sofosbuvir (Ledipasvir and sofosbuvir) AUC0-inf by approximately 2-fold, but did not significantly affect Sofosbuvir (Ledipasvir and sofosbuvir) Cmax. The exposures of GS-331007 and Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food.
Distribution: Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is >99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 0.51 and 0.66.
Sofosbuvir (Ledipasvir and sofosbuvir) is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1-20 mcg/mL. Protein-binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-Sofosbuvir (Ledipasvir and sofosbuvir) in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
Metabolism: In vitro, no detectable metabolism of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), systemic exposure was almost exclusively to the parent drug (>98%). Unchanged Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is the major species present in feces.
Sofosbuvir (Ledipasvir and 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 (Ledipasvir and sofosbuvir), GS-331007 accounted for approximately >90% of total systemic exposure.
Elimination: Following a single 90 mg oral dose of [14C]-Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life (t½) of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) following administration of Ledipasvir and sofosbuvir was 47 hrs.
Following a single 400 mg oral dose of [14C]-Sofosbuvir (Ledipasvir and sofosbuvir), mean total recovery of the dose was >92%, consisting of approximately 80%, 14% and 2.5% recovered in urine, feces and expired air, respectively. The majority of the Sofosbuvir (Ledipasvir and sofosbuvir) dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as Sofosbuvir (Ledipasvir and sofosbuvir). These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal t½ of Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007 following administration of Ledipasvir and sofosbuvir were 0.5 and 27 hrs, respectively.
Specific Populations: Patients with Renal Impairment: The pharmacokinetics of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) were studied with a single dose of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 90 mg in HCV-negative subjects with severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min by Cockcroft-Gault]. No clinically relevant differences in Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
The pharmacokinetics of Sofosbuvir (Ledipasvir and sofosbuvir) were studied in HCV-negative subjects 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 subjects with end-stage renal disorder (ESRD) requiring hemodialysis following a single dose of Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73 m2), the Sofosbuvir (Ledipasvir and 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 (Ledipasvir and sofosbuvir) and GS-331007 AUC0-inf was 28% and 1,280% higher when Sofosbuvir (Ledipasvir and sofosbuvir) was dosed 1 hr before hemodialysis compared with 60% and 2,070% higher when Sofosbuvir (Ledipasvir and sofosbuvir) was dosed 1 hr after hemodialysis, respectively. A 4-hr hemodialysis session removed approximately 18% of administered dose.
Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and 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 (Ledipasvir and sofosbuvir) and GS-331007. AUC and Cmax of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) exposures was not considered clinically relevant, as high response rates (SVR >90%) were achieved in male and female subjects across the phase 3 studies and the safety profiles are similar in females and males.
Children: The pharmacokinetics of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) or Sofosbuvir (Ledipasvir and sofosbuvir) in pediatric patients has not been established.
Elderly: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-80 years) analyzed, age did not have a clinically relevant effect on the exposure to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007.
Patients with Hepatic Impairment: The pharmacokinetics of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) were studied with a single dose of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 90 mg in HCV negative subjects with severe hepatic impairment (Child-Pugh class C). Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 had no clinically relevant effect on the exposure of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)).
The pharmacokinetics of Sofosbuvir (Ledipasvir and sofosbuvir) were studied following 7-day dosing of Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg 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 (Ledipasvir and 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 had no clinically relevant effect on the exposure of Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007.
Drug Interaction Studies: Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) are substrates of drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) while GS-331007 is not. P-gp inducers (eg, rifampin or St. John’s wort) may decrease Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) plasma concentrations, leading to reduced therapeutic effect of Ledipasvir and sofosbuvir and the use with P-gp inducers is not recommended with Ledipasvir and sofosbuvir. Co-administration with drugs that inhibit P-gp and/or BCRP may increase Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) plasma concentrations without increasing GS-331007 plasma concentration; Ledipasvir and sofosbuvir may be co-administered with P-gp and/or BCRP inhibitors. Neither Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) nor Sofosbuvir (Ledipasvir and sofosbuvir) is a substrate for hepatic uptake transporters organic cation transporter (OCT)1, OATP1B1 or OATP1B3. GS-331007 is not a substrate for renal transporters, including organic anion transporter OAT1 or OAT3 or OCT2.
Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) by CYP enzymes has been observed. Biliary excretion of unchanged Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is a major route of elimination. Sofosbuvir (Ledipasvir and sofosbuvir) is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with Ledipasvir and sofosbuvir mediated by CYP or UGT1A1 enzymes are not expected.
The effects of co-administered drugs on the exposure of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007 are shown in Table 8.
No effect on the pharmacokinetic parameters of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007 was observed with the combination of abacavir and lamivudine, or emtricitabine, rilpivirine, and tenofovir DF or raltegravir.
Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is an inhibitor of drug transporter P-gp and BCRP, and may increase intestinal absorption of co-administered substrates for these transporters. Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is an inhibitor of transporters OATP1B1, OATP1B3 and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1 and OCT1. The drug-drug interaction potential of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) in the systemic circulation is not expected due to its high protein-binding. Sofosbuvir (Ledipasvir and 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir) and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.
The effects of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) or Sofosbuvir (Ledipasvir and sofosbuvir) on the exposure of co-administered drugs are shown in Table 9.
No effect on the pharmacokinetic parameters of the following co-administered drugs was observed with Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) or Sofosbuvir (Ledipasvir and sofosbuvir): Abacavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone or rilpivirine.
Toxicology: Nonclinical Toxicology: Carcinogenesis and Mutagenesis: Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)): Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
Carcinogenicity studies of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) in mice and rats are ongoing.
Sofosbuvir (Ledipasvir and sofosbuvir): Sofosbuvir (Ledipasvir and sofosbuvir) was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Two-year carcinogenicity studies in mice and rats were conducted with Sofosbuvir (Ledipasvir and sofosbuvir). Mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 4- and 18-fold (in mice) and 8- and 10-fold (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose.
Impairment of Fertility: Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)): Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3-fold the exposure in humans at the recommended clinical dose. At the highest dose levels without effects, AUC exposure to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) was approximately 5- and 2-fold, in males and females, respectively, the exposure in humans at the recommended clinical dose.
Sofosbuvir (Ledipasvir and sofosbuvir): Sofosbuvir (Ledipasvir and sofosbuvir) had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 5-fold the exposure in humans at the recommended clinical dose.
Animal Toxicology and/or Pharmacology: Sofosbuvir (Ledipasvir and sofosbuvir):
Microbiology: Antiviral Activity: In HCV replicon assays, the median effective concentration (EC50) values of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009-0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004-0.007 nM; N=3). Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) has less antiviral activity compared to genotype 1 against genotypes 4a, 5a and 6a, with EC50 values of 0.39 nM, 0.15 nM and 1.1 nM, respectively. Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) has substantially lower activity against genotypes 2a, 2b, 3a and 6e with EC50 values of 21-249 nM, 16-530 nM, 168 nM and 264 nM, respectively.
In HCV replicon assays, the EC50 values of Sofosbuvir (Ledipasvir and sofosbuvir) against full-length replicons from genotypes 1a, 1b, 2a, 3a and 4a and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a or 6a ranged from 14-110 nM. The median EC50 value of Sofosbuvir (Ledipasvir and sofosbuvir) against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29-128 nM; N=67), 102 nM for genotype 1b (range 45-170 nM; N=29), 29 nM for genotype 2 (range 14-81 nM; N=15) and 81 nM for genotype 3a (range 24-181 nM; N=106). In replication competent virus assays, the EC50 values of Sofosbuvir (Ledipasvir and sofosbuvir) against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of Sofosbuvir (Ledipasvir and sofosbuvir) in combination with Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
Resistance: In Cell Culture: Hepatitis C virus replicons with reduced susceptibility to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a, conferred high levels of reduced susceptibility to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) (fold change in EC50 >1,000-fold).
Hepatitis C virus replicons with reduced susceptibility to Sofosbuvir (Ledipasvir and sofosbuvir) have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to Sofosbuvir (Ledipasvir and sofosbuvir) was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to Sofosbuvir (Ledipasvir and sofosbuvir).
In Clinical Trials: In a pooled analysis of subjects who received Ledipasvir and sofosbuvir in phase 3 trials, 37 subjects (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep sequencing data (assay cutoff of 1%) were available for 37/37 and 36/37 subjects' viruses, respectively.
Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M or Y93H/N at failure. Five (5) of these 16 subjects also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N and L31M.
Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Three (3) of these 7 subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H.
At failure, 38% (14/37) of virologic failure subjects had ≥2 NS5A substitutions at resistance-associated positions.
In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)).
Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with Sofosbuvir (Ledipasvir and sofosbuvir) failure were detected in the phase 3 trials. In addition, NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2) and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV GT1a. The D61G substitution was previously described in subjects infected with HCV GT1a in a liver pre-transplant trial. The clinical significance of these substitutions is currently unknown.
The Sofosbuvir (Ledipasvir and sofosbuvir)-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the phase 3 trials. Nonstructural protein 5B substitutions S282T, L320V/I and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following 8 weeks of treatment with Ledipasvir and sofosbuvir in a phase 2 trial.
Cross Resistance: Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) was fully active against the Sofosbuvir (Ledipasvir and sofosbuvir) resistance-associated substitution S282T in NS5B while all Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) resistance-associated substitutions in NS5A were fully susceptible to Sofosbuvir (Ledipasvir and sofosbuvir). Both Sofosbuvir (Ledipasvir and sofosbuvir) and Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions eg, NS5B non-nucleoside inhibitors and NS3 protease inhibitors. Nonstructural 5A substitutions conferring resistance to Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) may reduce the antiviral activity of other NS5A inhibitors. The efficacy of Ledipasvir and sofosbuvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.
Persistence of Resistance-Associated Substitutions: No data are available on the persistence of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) or Sofosbuvir (Ledipasvir and sofosbuvir) resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients.
Effect of Baseline HCV Polymorphisms on Treatment Response: Analyses were conducted to explore the association between preexisting baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the phase 3 trials, 23% (370/1,589) of subjects’ virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92 or 93) identified by population or deep sequencing.
In treatment-naive subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in studies ION-1 and ION-3, relapse rates were 6% (3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with Ledipasvir and sofosbuvir. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks treatment with Ledipasvir and sofosbuvir.
In treatment-experienced subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with Ledipasvir and sofosbuvir.
The specific baseline NS5A resistance-associated polymorphisms observed among subjects with relapse were M28T/V, Q30H, Q30R, L31M, H58P, Y93H and Y93N in genotype 1a, and L28M, A92T and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates.
Sustained virologic response was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to NS5B nucleoside inhibitors. The Sofosbuvir (Ledipasvir and sofosbuvir) resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject in phase 3 trials by population or deep sequencing.
How should I take Ledipasvir and sofosbuvir?
Take Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
To help clear up your infection completely, Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) combination must be taken for the full time of treatment, even if you begin to feel better after a few days. Also, it is important to keep the amount of medicine in your body at a steady level. To help keep the amount constant, Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) must be used on a regular schedule.
Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) should come with a patient information leaflet. Read and follow the information carefully. Ask your doctor if you have any questions.
You may take Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) with or without food.
If you are taking an antacid containing aluminum or magnesium hydroxide, take it 4 hours before or after taking Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) combination.
Dosing
The dose of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir). If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- For hepatitis C virus infection:
- Adults—One tablet once a day, taken for 12 or 24 weeks. Each tablet contains Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 90 milligrams (mg) and Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg.
- Children—Use and dose must be determined by your doctor.
- For hepatitis C virus infection:
Missed Dose
If you miss a dose of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir), take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Do not take more than 1 tablet per day.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Keep the medicine in the original bottle that you were given at the pharmacy.
Ledipasvir and sofosbuvir administration
Oral:
Tablets: Administer with or without food.
Pellets: Administer with or without food. If administered without food, pour packet contents directly in the mouth and swallow without chewing to avoid bitter aftertaste; follow with water if needed. If administered with food, sprinkle packet contents on ≥1 spoonful of nonacidic soft foods (eg, pudding, chocolate syrup, mashed potatoes, ice cream) at or below room temperature; gently mix. Swallow entire contents within 30 minutes of mixing; do not chew to avoid bitter aftertaste.
Ledipasvir and sofosbuvir pharmacology
Mechanism Of Action
Ledipasvir and sofosbuvir is a fixed-dose combination of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir) which are direct-acting antiviral agents against the hepatitis C virus.
Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) and Sofosbuvir (Ledipasvir and sofosbuvir).
The effect of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) does not prolong QTc interval to any clinically relevant extent.
The effect of Sofosbuvir (Ledipasvir and sofosbuvir) 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, Sofosbuvir (Ledipasvir and sofosbuvir) does not prolong QTc to any clinically relevant extent.
Pharmacokinetics
Absorption
The pharmacokinetic properties of Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and 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, Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir (Ledipasvir and 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) (N=2113), Sofosbuvir (Ledipasvir and sofosbuvir) (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-state Cmax for Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)), Sofosbuvir (Ledipasvir and sofosbuvir), and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir (Ledipasvir and 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 (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased Sofosbuvir (Ledipasvir and sofosbuvir) AUC0-inf by approximately 2-fold, but did not significantly affect Sofosbuvir (Ledipasvir and sofosbuvir) Cmax. The exposures of GS-331007 and Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) 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 with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food.
Distribution
Ledipasvir (Ledipasvir and Sofosbuvir (Ledipasvir and sofosbuvir)) is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior to reaching the 12 week post-treatment follow-up visit.
There were 7 subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm, and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with Ledipasvir and sofosbuvir + RBV for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre-and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.
References
- DailyMed. "LEDIPASVIR; SOFOSBUVIR: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Ledipasvir: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Ledipasvir: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
