Ledipasvir/sofosbuvir
Medication used to treat hepatitis C From Wikipedia, the free encyclopedia
Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C.[8] It is a fixed-dose combination of ledipasvir and sofosbuvir.[8] Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1.[9] Some evidence also supports use in HCV genotype 3 and 4.[9] It is taken daily by mouth for 8–24 weeks.[8]
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| Combination of | |
|---|---|
| Ledipasvir | NS5A inhibitor |
| Sofosbuvir | NS5B (RNA polymerase) inhibitor |
| Clinical data | |
| Trade names | Harvoni, Hepcinat-LP, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a614051 |
| License data | |
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| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
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| Identifiers | |
| PubChem CID | |
| KEGG | |
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| Chemical and physical data | |
| Formula | C71H83F3N11O15P |
| Molar mass | 1418.476 g·mol−1 |
| 3D model (JSmol) | |
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It is generally well tolerated.[10] Common side effects include muscle pains, headache, nausea, rash, and cough.[8] It is unclear if use in pregnancy is safe for the baby.[8] Ledipasvir works by decreasing the activity of NS5A and sofosbuvir works by decreasing the activity of NS5B polymerase.[8]
Ledipasvir/sofosbuvir was approved for medical use in the United States, in the European Union, and in Canada in 2014.[8][11][7][12][13] It is on the World Health Organization's List of Essential Medicines.[14]
Medical uses
Summarize
Perspective
Cure rates are 94% to 99% in people infected with genotype 1 (46% of HCV cases).[15] It has also been evaluated for the treatment of infection with other hepatitis C genotypes, and has shown promising results in genotypes 3 and 4 (making up 30% and less than 22% of HCV cases respectively).[9][6][16][15]
Resistance
NS5A mutations
Multiple mutations of HCV replicons are necessary to cause a significant effect in resistance due to multiple mechanisms of action.[17] In general, HCV genotype 1a is less resistant to mutation than genotype 1b.[18]
For genotype 1b a single amino acid substitution (e.g. L31V) in the replicon had less than a 100 fold increase in resistance to the ledipasvir in Harvoni, while a two amino acid substitution had over a 1000 fold increase in resistance.[18][19] Genotype 1a had a similar but more substantial increase in resistance with each respective increase in amino acid substitution with resistance associated substitutions at K24R, M28T/V, Q30R/H/K/L, L31M, and or Y93H/N.[6]
NS5A polymorphisms also have an effect on viral resistance with the most common resistance-associated amino acid substitutions detected at Q30R, Y93H or N, and L31M in patients with a rapid virological response (RVR).[6] The specific baseline NS5A resistance-associated polymorphisms observed in clinical trials were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a and L28M, A92T, and Y93H in genotype 1b.[6] Patients with multiple baseline NS5A polymorphisms tend to have higher relapse rates when using ledipasvir/sofosbuvir.[6] The difference in relapse rates between treatment naive and treatment experience groups with baseline NS5A polymorphisms ranges from 1% after a 12-week regimen and 0% after a 24-week regimen respectively.[18][6]
NS5B mutations
A single amino acid substitution S282T contributes to viral resistance and decreases the activity of sofosbuvir in ledipasvir/sofosbuvir by approximately 2 to 18 fold.[18][20]
Cross resistance
No cross resistance was seen in the combination of ledipasvir and sofosbuvir in ION phase 1,2 and, 3 clinical trials as ledipasvir was fully active against sofosbuvir-resistance-associated substitutions and vice versa.[6][21]
Side effects
More than 10% of people taking ledipasvir/sofosbuvir have headaches or fatigue; rashes, nausea, diarrhea, and insomnia occur in between 1% and 10% of people taking it.[6][5]
More severe reactions are connected with allergic reactions to the medications and cardiovascular problems. Harvoni side effects are considered relatively mild compared to older interferon-based treatment.[citation needed]
Ledipasvir/sofosbuvir could cause hepatitis B re-activation in people co-infected with hepatitis B and C viruses. The European Medicines Agency recommended screening all people for hepatitis B before starting ledipasvir/sofosbuvir for hepatitis C in order to minimize the risk of hepatitis B reactivation.[22]
Drug interactions
Ledipasvir/sofosbuvir is a substrate for the drug transporters P-Glycoprotein (P-gp) and breast cancer resistance protein (BCRP).[18] Intestinal absorption of these drug transporter substrates may be decreased by inducers such as rifampin and St. John's wort .[23]
Patients are also advised to stay away from H2 receptor antagonists (H2RA) and proton-pump inhibitors (PPI) because they decrease the concentration of ledipasvir (its solubility is pH-dependent and is higher under acidic conditions). Therefore, it is advised to take a PPI at least two hours after ledipasvir/sofosbuvir with a dose less than or equal to 20 mg daily and H2RAs with a dose of less than or equal to 40 mg twice daily.[18][24]
Ledipasvir/sofosbuvir should additionally be avoided when taking amiodarone or other drugs that lower heart rate; there is a serious risk of the heart slowing or stopping when ledipasvir/sofosbuvir is used with such drugs.[6][5]
Mechanisms of action
The most commonly associated mechanism associated with ledipasvir/sofosbuvir is the hyperphosphorylation of NS5A, a viral polymerase important in proper viral assembly and interferes with proper liver metabolism.[25] Ledipasvir/sofosbuvir inhibits the proper viral assembly by re-positioning NS5A's sub-cellular localization.[18]
NS5B, a viral polymerase that can initiate RNA synthesis de novo, is also allosterically inhibited by ledipasvir/sofosbuvir.[26]
NS5A and NS5B inhibitors in combination have a synergistic effect.[27]
Pharmacokinetics
Summarize
Perspective
Sofosbuvir is absorbed fast in the plasma with a peak concentration (Cmax) at 0.8 to 1 hour after the administered dosage and undergoes extra hepatic metabolism with 61 to 65% bound to human plasma proteins.[28][18] It is then predominantly converted to the inactive phosphate free circulating metabolite GS-331007 (eliminated 76% through renal passive filtration) which has a median peak plasma concentration at 3.5 to 4 hours after the medication is ingested.[6] Sofosbuvir does not appear to be affected by different levels of macronutrients when compared with fasting states.[29]
Ledipasvir has a maximum concentration at 4 to 4.5 hours after ingestion and is not affected by macronutrients.[18][6] It is more than 98% protein bound and is predominantly eliminated fecally, with minimal metabolism in the liver.[6]
Elimination
The median terminal half life after a dosage of ledipasvir/sofosbuvir for 90 mg of [14C]-Ledipasvir is 47 hours; for 400 mg of [14C]-Sofosbuvir it is 0.5 hours (after the initial distribution of medication in body tissue) and 27 hours (the eventual excretion of the medication).[6][30]
| Substance | ng/mL |
|---|---|
| Ledipasvir | 323 |
| Sofosbuvir | 618 |
| GS-331007 | 707 |
Note: The maximum concentration is 32% higher in healthy individuals than those infected with Hepatitis C.[6]
| Substance | ng*hr/mL |
|---|---|
| Ledipasvir | 7290 |
| Sofosbuvir | 1320 |
| GS-33107 | 12,000 |
Note: The maximum concentration is 24% higher in healthy individuals than those infected with Hepatitis C.[6]
Blood detection
An analytical method based on LC tandem MS has been developed for the simultaneous extraction and determination of ledipasvir/sofosbuvir in human plasma using antiviral daclatasvir as an internal standard. Average extraction recoveries for sofosbuvir and ledipasvir were 91.61% and 88.93% respectively.[31]
Society and culture
One manufacturer is Gilead Sciences.[8]
References
External links
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