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Combination formulation: Harvoni® (ledipasvir/sofosbuvir), GS-5885
Ledipasvir prevents replication of the hepatitis C virus (HCV) by targeting non-structural protein 5A (NS5A) protein. Although the precise mechanism is poorly understood, data suggest inhibition of NS5A leads to blockade of hyperphosphorylation, which plays an essential role in viral replication.
Activity
Ledipasvir is only approved for the treatment of chronic infection caused by genotype 1 HCV. The safety and efficacy of ledipasvir has not been fully established for genotypes 2, 4, 5 or 6. Ledipasvir/sofosbuvir has only been studied in a phase II open-label trial in treatment-naïve patients with genotype 3.
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Primarily excreted ( > 98% ) unchanged in the feces, with little renal excretion.2312
Not an inhibitor or inducer of P450 or UGT. Likely a substrate of P-gp. Weak inhibitor of P-gp and BRCP (intestinal, not systemic). Likely a weak inhibitor of OATP1B1/1B3.2319
Variables such as age, body weight, gender, race, cirrhosis, ribavirin usage, and disease status do not have a clinically relevant impact on ledipasvir exposures in HCV-infected subjects.2400
Ledipasvir is commercially available as Harvoni®, a single tablet coformulation of ledipasvir 90 mg and sofosbuvir 400 mg
In a retrospective case series of 10 patients (60% HCV GT1a) on SOF/VEL (50%), LED/SOF (30%) and GLE/PIB (20%), patients either crushed (70%) or split (30%) their DAA tablets. All patients were prescribed 12 weeks of DAA therapy and had undetectable HCV viral loads by day 56. All patients with available data (7/7) had SVR12; 3 patients had undetectable viral loads at end of treatment but no follow-up data were available. No patients experienced severe adverse events.3560
A patient with HIV, hepatitis C and high-grade postresection sarcoma of the throat received crushed ledipasvir/sofosbuvir daily for 12 weeks and achieved SVR. The ledipasvir/sofosbuvir was crushed and dissolved in water and administered via PEG tube.(Huffman V et al. Am J Health-Syst Pharm 2020;78:36-40.)
In a treatment-experienced patient with compensated cirrhosis, SVR12 was achieved after 24 weeks of treatment with crushed ledipasvir/sofosbuvir administered via a percutaneous endoscopic gastrostomy (PEG) tube.3209
A 19-year old woman with HCV genotype 1 and HIV coinfection achieved SVR12 after 12 weeks of crushed ledipasvir/sofosbuvir administered via gastrosomy button. Each ledipasvir/sofosbuvir tablet was crushed, mixed with 10 mL warm water, and administered via syringe. Additional warm water was used to obtain all the powder.3210
Indication: Genotype 1 chronic hepatitis C mono-infection in adults with compensated liver disease | ||
| Dosage | Duration |
Adults who are treatment-naive | ||
with or without cirrhosis | One tablet daily | 12 weeks* |
*Treatment-naive patients without cirrhosis who have HCV RNA | ||
Adults who are treatment-experienced# | ||
without cirrhosis | One tablet daily
| 12 weeks |
with cirrhosis | 24 weeks | |
Note: tablet contains fixed dose of ledipasvir and sofosbuvir, taken by mouth, with or without food #Treatment experienced patients are defined as those who have failed treatment with either: 1) a regimen of peginterferon alfa and ribavirin, or 2) a regimen of an HCV protease inhibitor and peginterferon alfa and ribavirin. | ||
Canadian labeling:
Missed dose: If missed dose is within 18 hours of regularly scheduled time, administer as soon as possible; if >18 hours from regularly scheduled time, resume at next regularly scheduled dose (do not double dose). If patient vomits 5 hours, resume administer at next regularly scheduled dose.
The safety and efficacy of ledipasvir has not established in pediatric patients.
Similar pharmacokinetic parameters post-administration of a single 90 mg dose of ledipasvir were seen between subjects with severe renal impairment (eGFR < 30 ml/min) and those with normal renal function. No dosage adjustment is required for patients with mild, moderate or severe renal impairment.3133
End stage renal disease (ESRD), including intermittent hemodialysis (IHD): Specific guidelines for dosage adjustments in these patients are not available.
The kinetics of single and multiple-dose ledipasvir were evaluated in HCV-uninfected subjects with moderate (Child Pugh class B) or severe hepatic (Child Pugh class C) impairment. No clinically relevant changes in ledipasvir AUC were observed in moderate or severe hepatic impairment compared to matched subjects with normal hepatic function. Ledipasvir Cmax ↓ 36% and t1/2 was modestly prolonged in subjects with severe hepatic impairment, possibly due to lower absorption/bioavailability and reduced clearance. There was no effect of severe hepatic impairment on ledipasvir plasma protein binding. Study drugs were well tolerated.2350
Dose adjustment of ledipasvir in patients with mild, moderate, or severe hepatic impairment is not required.
Decompensated cirrhosis: There are no dosage adjustments provided in manufacturer’s labeling. Safety and efficacy have not been established in patients with decompensated liver disease.
No impact of moderate-fat or high-fat meal vs fasting on ledipasvir pharmacokinetics. Ledipasvir/sofosbuvir may be taken with or without food.2395
In a case report, a non-cirrhotic 42 yo female with HCV GT1A was treated with sofosbuvir/ledipasvir. Three years prior to treatment, she had a RYGB surgery. During her treatment, she experienced headaches and increased GERD, which was treated with pantoprazole 20mg daily. HCV viral load suppressed three weeks after starting treatment. SVR was confirmed 16 weeks after treatment completion. No serum levels were measured. 3400
In general, the drug-drug interaction potential with ledipasvir is primarily limited to the process of intestinal absorption. Clinically relevant inhibition by ledipasvir in systemic circulation is not expected owing to a high degree of protein binding.
Based on drug-interaction studies, no clinically relevant interactions are expected with the following select agents:
- ARVs: NRTIs (abacavir, lamivudine, emtricitabine, tenofovir/TDF*), NNRTIs (efavirenz, rilpivirine), boosted-PIs (atazanavir/ritonavir, darunavir/ritonavir), or raltegravir
- Per U.S. product monograph, patients receiving ledipasvir as part of Harvoni concomitantly with Stribild or tenofovir DF and a boosted-PI should be monitored for tenofovir-associated reactions
- Immunosuppressants: cyclosporine, tacrolimus
- Narcotics: methadone
- Statins: pravastatin
- Oral contraceptives
Potential for ledipasvir to affect concentrations of other drugs:
Ledipasvir inhibits:
- P-gp and BCRP, which may increase intestinal absorption of coadministered substrates of these transporters
- Digoxin: therapeutic concentration monitoring of digoxin is recommended with co-administration of ledipasvir
- OATPP1B1 or OATPP1B3, BSEP and UGT1A1, but only at concentrations exceeding those achieved in clinic
Potential for other drugs to affect concentrations of ledipasvir:
Potent P-gp inducers in the intestine (i.e., rifampin)
- May significantly reduce ledipasivr plasma concentrations
- Concurrent administration is not recommended with the following agents:
- Anticonvulsants: carbamazepine, phenytoin, phenobarbital or oxcarbazepine
- Antimycobacterials: rifampin, rifabutin
- John’s wort
Acid reducing agents
- May decrease ledipasvir solubility (secondary to increases in pH)
- Antacids: separate administration of ledipasvir by 4 hours
- H2-receptor antagonists:
- Administer with or 12 hours apart from ledipasvir;
- Do NOT exceed doses equivalent to famotidine 40 mg twice daily
- Proton pump inhibitors:
- Do NOT administer before ledipasvir
- Do NOT exceed doses equivalent to omeprazole 20 mg
P-gp and BCRP inhibitors
- No clinically significant interaction noted in clinical trials when ledipasvir/sofosbuvir was administered with darunavir/ritonavir (P-gp inhibitors) or cyclosporine (a P-gp and BCRP inhibitor).
- May be coadministered with ledipasvir (per FDA-labeling)
Oral Bioavailability:
Ledipasvir is well-absorbed.
Protein Binding:
Following administration of a single 90 mg dose, ledipasvir is greater than 99.8% bound to human plasma proteins, with a blood/plasma ratio of 0.51 to 0.66.
Vd:
N/A; however, in animal studies, 14C-ledipasvir-derived radioactivity was widely distributed to tissues after a single oral dose.
Tmax:
Following oral administration, the time to peak plasma concentration of ledipasvir is 4 to 4.5 hours.
Intracellular T½:
The mean terminal half-life of ledipasvir is approximately 47 hours
Metabolism:
Although the exact mechanism remains unknown, evidence suggests ledipasvir undergoes slow oxidative metabolism to form the metabolite M19.
There does not appear to be any appreciable metabolism by CYP and UGT1A1 enzymes.
Systemic exposure appears to be almost exclusively parent drug.
Ledipasvir is also a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP). However, it is not a substrate for any known hepatic uptake transporters (including OCT1, OATPP1B1 or OATPP1B3).
Not an inhibitor or inducer of P450 or UGT.
Weak inhibitor of P-gp and BRCP (intestinal, not systemic). Likely a weak inhibitor of OATP1B1/1B3.2319
Excretion:
- Elimination occurs primarily via the biliary route, resulting in 86% recovery in the feces (with approximately 70% of the administered dose as the unchanged parent drug and 2.2% as M19).
- Only 1% of the dose is renally eliminated (in urine).2312
Relative to healthy subjects, the mean steady-state AUC0-24 and Cmax was 24% and 32% lower, respectively, in HCV-infected patients,
- Mean steady-state AUC0-24 : 7290 ngxhr/mL
- Mean steady-state Cmax: 323 ng/mL
Variables such as age, body weight, gender, race, cirrhosis, ribavirin usage, and disease status do not have a clinically relevant impact on ledipasvir exposures in HCV-infected subjects.2400
Genotype | Effective Concentration (50% reduction, EC50) Values |
1a | Median EC50 = 0.018 nM (range 0.009-0.085 nM) 0.031 nM (in HCV replicon assays) |
1b | Median EC50 = 0.006 nM (range 0.004-0.007 M) 0.004 nM (in HCV replicon assays) |
2a | EC50 = 21 nM (against replicons with L31 in NS5A) EC50 = 249 nM (against replicons with M31 in NS5A) |
2b | EC50 = 16 nM EC50 = 530 nM (against replicons with M31 in NS5A) |
3 | EC50 = 168 nM |
4a | EC50 = 0.39 nM |
5a | EC50 = 0.15 nM |
6a | EC 50 = 1.1 nM |
N/A; however, low levels of C14-ledipasvir-derived radioactivity were observed in the CNS.
U.S. Food and Drug Administration's Pregnancy Category: B (all trimesters)
Studies evaluating ledipasvir use during human pregnancy have not been conducted. It is unknown if ledipasvir crosses the placenta. In animal-reproduction studies, administration of ledipasvir did not produce observable effects on fetal development at the highest doses tested. Pharmacokinetic data suggest at the recommended clinical dose, AUC exposure to ledipasvir in animals was between 2- and 4-fold the human exposure.
Lactation
Based on currently available evidence, the potential for toxicity in a newborn/infant cannot be excluded. Lactation studies with ledipasvir have not been conducted. Data from animal studies, however, indicate that ledipasvir was detectable in the milk of lactating rats, albeit with no observable effect on the nursing pups.
Per U.S. labeling recommendations, the decision to breastfeed during therapy should take into account the risk of infant drug exposure and the benefits of treatment to the mother. Per Canadian labeling, however, mothers should be instructed to discontinue breastfeeding prior to initiating therapy with ledipasvir.
In cell culture
In cell cultures, NS5A amino acid substitutions Y93H (in genotypes 1a and 1b) and Q30E (genotypes1a) significantly reduced susceptibility to ledipasvir (greater than a 1000-fold change in the Median Effective Concentration, or EC50).
In clinical studies
In Phase III clinical trials, 37 subjects experienced virologic failures with ledipasvir/sofosbuvir. Emergent NS5A resistance-associated substitutions were seen in 76% (n=22/29) of subjects with genotype 1a virus, and in 88% (n=7/8) with genotype 1b virus. Among subjects with genotype 1a, the most common substitutions identified at failure were Q30R, Y93H or N, and L31M. Among those with genotype 1b (88%, n = 7/8), the most common substitution identified at failure was Y93H. Other detected substitutions included: K24R, M28T/V, Q30H/K/L (genotype 1a) and L31V/M/I (genotype 1b).
Persistence of resistance mutations
In patients who received 3 day monotherapy treatment with ledipasvir, HCV NS5A resistant polymorphisms (present at baseline or selected during treatment) persisted in 100% of genotype 1a and 50% of genotype 1b-infected patients at 48 weeks following treatment cessation, suggesting long-term persistence of resistance.3132,3135
Phenotypic analyses demonstrated that the identified NS5A substitutions conferred a 20- to > 243-fold reduction in susceptibility to ledipasvir; however, viruses with these resistance-associated variants remained susceptible to sofosbuvir.
Cross-resistance is not expected between ledipasvir and other classes of direct-acting antivirals with different mechanisms of action. Ledipasvir was fully active against sofosbuvir resistance (including substitution S282T in NS5B) and vice versa. Ledipasvir was also fully active against resistance-associated variants commonly known to other classes of HCV inhibitors, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors, and ribavirin. However, efficacy of ledipasvir has not been demonstrated if previous treatment failure was associated with an NS5A inhibitor regimen.
Ledipasvir-associated resistance mutations confer cross-resistance to other first generation HCV NS5A inhibitors.2929
Adverse Events
Common (incidence >10%):
- Neurologic: headache (11-17%);
- Other: fatigue (13-18%)
Lab Abnormalities
In adult clinical trials with Genotype 1 HCV with compensated liver disease:
- High lipase level in serum, (>3 x ULN): incidence 1-3%
- Elevated serum bilirubin (>1.5 x ULN): incidence 1-3%
Effects on EKG
- Results of a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover trial (n=59) indicated that ledipasvir (120 mg twice daily for 10 days) did not have a significant effect on QTc interval prolongation.
Baseline Assessment
- Determination of hepatitis C genotype (prior to initiation of therapy)
- Serum HCV-RNA
Laboratory parameters: bilirubin, liver enzymes and serum creatinine
Routine Labs
Serum HCV-RNA: during treatment, at the end of treatment, during treatment follow-up and as clinically indicated.
Bilirubin, liver enzymes, and serum creatinine: periodically and as clinically indicated.
Store below 30 degrees C (86 degrees F)
Gilead Sciences