Simeprevir
Simeprevir Uses, Dosage, Side Effects, Food Interaction and all others data.
Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated in patient's with HCV genotype 1 for the treatment of chronic hepatitis C virus (HCV) infection. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . Like all NS3/4A inhibitors, simeprevir is a serine protease inhibitor in similarity to Boceprevir and Telaprevir but is classified as a second generation protease inhibitor. This class of antiviral drugs were the first direct acting antivirals approved but are associated with lower cure rates than newer drugs. Broad use of simeprevir occurred when it was used in combination with a newer drug, Sofosbuvir. Inhibiting HCV NS3/4A protease in a potent and highly specific manner, simeprevir is a direct-acting antiviral agent against the hepatitis C virus. Since the viral protease NS3/4A complex is essential for cleaving the HCV encoded polyprotein into individual viral proteins facilitating replication , the drug blocks the viral replication process. It is shown to display synergistic effects with interferon-α and HCV NS5B inhibitor, and additive effects with ribavirin in HCV replicon cells . Unlike first generation serine protease inhibitors, simprevir has a sightly different resistance profile where limited therapeutic efficacy of the drug is observed with NS3 Q80K polymorphic variants and simeprevir-specific amino acid position of 168 also results in higher treatment failure rates . The observed prevalence of the N3 Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b .
According to 2017 American Association for the Study of Liver Diseases (AASLD) and 2015 consensus guidelines from the Canadian Association for the Study of the Liver (CASL), simeprevir can be used as first-line or second-line threapies for treatment-naïve patients as adjunct to sofosbuvir treatment for genotype 1 or PEG-Interferon/ribavirin combination therapy for genotype 1 or 4. The combination therapy of simeprevir and other antiviral agents are initiated in HCV-positive patients with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .
Simeprevir was approved by the FDA in November 2014 and is marketed under the brand name Olysio as oral tablets. Administered once daily with food, 150mg simeprevir capsule is used in combination with Sofosbuvir in patients with HCV genotype 1 without cirrhosis for 12 week duration. In patients with HCV genotype 1 with compensated cirrhosis, the treatment is directed for 24 week duration. Sustained virologic response 12 weeks after planned end of treatment (SVR12) was achieved in 170/176 (97%) subjects without cirrhosis treated with 12 weeks simeprevir in combination with sofosbuvir (FDA Label). The overall SVR12 was 88% (44/50) in treatment-naïve patients with cirrhosis .
| Trade Name | Simeprevir |
| Availability | Discontinued |
| Generic | Simeprevir |
| Simeprevir Other Names | Simeprevir |
| Related Drugs | Epclusa, Mavyret, ribavirin, Harvoni, Sovaldi, Vosevi |
| Type | Oral |
| Formula | C38H47N5O7S2 |
| Weight | Average: 749.939 Monoisotopic: 749.291690263 |
| Protein binding | Simeprevir is extensively (99.9%) bound to plasma proteins, mainly to albumin and to a lesser extent, alpha 1-acid glycoprotein. Increased plasma concentration due to drug-drug interactions is expected when co-administering moderate or strong inhibitors of CYP3A, while the opposite effect is predicted from co-administration of moderate or strong inducers of CYP3A. |
| Groups | Approved |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Simeprevir is a direct-acting antiviral agent that inhibits HCV NS3/4A protease to treat chronic hepatitis C virus (HCV) infection in adults with HCV genotype 1 or 4.
Indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection: typically in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis and in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.
Resistance: Reduced susceptibility to simeprevir was most commonly associated with the viral NS3 Q80K polymorphism. Amino acid substitutions at NS3 positions S122, R155 and/or D168 are also shown to reduce susceptibility to simeprevir in genotype 1a/b patients.
Simeprevir is also used to associated treatment for these conditions: Chronic Hepatitis C Genotype 1, Chronic hepatitis C genotype 4
How Simeprevir works
Simeprevir is accumulated in the liver after uptake into hepatocytes via OATP1B1/3. NS3/4A heterodimeric complex is composed of the cofactor N4A subunit and N3 subunit which contains the proteolytic site. The NS3/4A protease cleaves the HCV polyprotein downstream of the NS3 site, generating non-structural viral proteins NS3, NS4A, NS4B, NS5A and NS5A and subsequently formation of mature proteins . Simeprevir exerts an inhibitory action on HCV polyprotein cleavage via induced-fit binding to an extended S2 subsite located in the NS3 catalytic site . NS3/4A inhibitors usually depend on few interactions located in the substrate binding groove of the viral serine protease, thus are susceptible to resistance and failed treatment from few critical mutations in these sites. At higher concentration above their antiviral half-maximal effective concentration (EC50), simeprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins (MAVS otherwise known as IPS-1, VISA, or Cardif) and toll/interleukin-1 receptor (TIR)- domain-containing adaptor-inducing IFN-β (TRIF). Blocking the function of these adaptor proteins results in impaired interferon induction. NS3/4A inhibitors recover the proper IFN-signaling pathways .
Toxicity
In a combination therapy with sofosbuvir, most common reported adverse effects is fatigue, headache and nausea. In case of triple therapy with PEG-Interferon Alfa-2A and ribavirin, most common adverse effects included rash (including photosensitivity), pruritus and nausea. Elevations of serum bilirubin may be observed due to inhibition of bilirubin transporters OATP1B1 and MRP2 by simeprevir.
Food Interaction
- Take with food.
[Moderate] ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of simeprevir, although the type of food does not seem to matter.
In healthy study subjects, administration of simeprevir after a high-fat, high-caloric (928 kcal) breakfast increased systemic exposure (AUC) by 61% and delayed absorption by 1 hour, while administration after a normal caloric (533 kcal) breakfast increased AUC by 69% and delayed absorption by 1.5 hours.
MANAGEMENT: To ensure maximal oral absorption, simeprevir should be administered with food.
Simeprevir Drug Interaction
Major: dexamethasoneModerate: diltiazemUnknown: amphetamine / dextroamphetamine, fexofenadine, allopurinol, donepezil, aspirin, lorazepam, amoxicillin / clavulanate, sulfamethoxazole / trimethoprim, mupirocin topical, betamethasone, citalopram, Allergy , loratadine / pseudoephedrine, docusate, losartan, duloxetine, glucose, acetaminophen
Volume of Distribution
The volume of distribution for simeprevir has yet to be determined. In animal studies, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues.
Elimination Route
The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir capsule in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours following the oral administration.
Half Life
The elimination half-life of simeprevir following 200mg dose administration is about 41 hours in HCV-positive patients and 10 to 13 hours in individuals without HCV infection.
Clearance
The clearance of simeprevir has yet to be determined.
Elimination Route
Simeprevir is predominantly eliminated through biliary excretion. In a radioactivity study, 91% of radiolabeled drug was detected in the feces and less than 1% was detected in the urine. From the recovered drug in the feces, the unchanged form of simeprevir accounted for 31% of the total administered dose.
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