Simeprevir

Overview

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.[1–4] WP

Common side effects include feeling tired, headache, rash, itchiness, and sensitivity to sunlight. In those with previous hepatitis B infection, active disease may recur. It is not recommended in those with significant liver problems. During pregnancy when used with ribavirin it may cause harm to the baby while when used with sofosbuvir its safety is unclear. Simeprevir is a HCV protease inhibitor.[1][5] WP

Simeprevir was developed by Medivir AB and Janssen Pharmaceutica. It was approved for medical use in the United States in 2013. It was removed from the World Health Organization's List of Essential Medicines in 2019. It is not available as a generic medication as of 2015.[5–9] WP

Uses, dosage and effects

Medical use

Simeprevir is indicated treating chronic hepatic C (CHC) infection as a part of a triple antiviral treatment regimen consisting of two other drugs: peginterferon-alfa (PEG-IFN) and ribavirin (RBV). It is primarily effective in treating Hepatitis C virus (HCV) genotype 1 infected subjects with compensated liver disease, including cirrhosis. There are currently no studies that show Simeprevir's effectiveness as a single therapy for HCV. Simeprevir is generally used for HCV genotype 1 infected subjects, but off-label medical use has been indicated for type 4 genotype as well.[10][11] WP

Dosing

Simeprevir is dosed along with peg-IFN and RBV as triple therapy. Appropriate dosing of Simeprevir is dependent upon the patient's liver function, kidney function, viral load, and HCV genotype. This medication is not recommended for people with moderate or severe liver impairment and people with end-stage kidney disease since Simprevir was not studied for use in these patient populations. Simeprevir might be discontinued depending on their viral load. For instance, if the patient's viral load is detectable (>25 units/mL) during the 4th week of their treatment regimen, it is considered an inadequate treatment and simeprevir must be discontinued.[10] WP

Combination treatment

In March 2015, Gilead Sciences e-mailed warnings to health care providers about nine people that began taking its hepatitis C drugs ledipasvir/sofosbuvir or sofosbuvir along with amiodarone, daclatasvir, or simeprevir developed abnormally slow heartbeats and one died of cardiac arrest. Three required a pacemaker to be inserted. Gilead said the combinations aren't recommended and product labels will be updated.[12] WP

Risks and side effects

Contraindications

Any contraindications that apply to peg-IFN and RBV apply to simeprevir since they must be used in combination during treatment of CHC. For example, people with sickle cell anemia are contraindicated to RBV therapy and are therefore contraindicated to simeprevir and peg-IFN combination therapy. Pregnant women and men whose female partners are pregnant are contraindicated for simeprevir since peg-IFN and RBV are known to cause birth defects.[10][13][14] WP

Pregnancy

Simeprevir is avoided in pregnant women or women planning to be pregnant because it going to be taken with RBV and Peg-IFN, which have both shown to cause fetal problems in animal studies. RBV has been shown to cause birth defects and fetal deaths in animal studies. Peg-IFN has been shown to cause abortions in animal studies. People must have a negative pregnancy test prior to starting therapy, use at least two effective birth control methods during treatment, and undergo monthly pregnancy tests. If pregnant women are exposed to any medication regimen containing ribavirin, they are encouraged to report this through the ribavirin pregnancy registry.[10][13][14] WP

Adverse effects

Severe itching (22%), sensitivity to sunlight (5%), and rash (25%) are some of the common adverse effects of simeprevir. Other side effects may include nausea, muscle pain, difficulty breathing and increased bilirubin. It may reactivate hepatitis B in those who have been previously infected. The European Medicines Agency (EMA) has recommended screening all people for hepatitis B before starting simeprevir for hepatitis C in order to minimize the risk of hepatitis B reactivation.[15–18] WP

Interactions

Drug interactions

Simeprevir is a CYP3A4 substrate so its plasma concentration will significantly increase if taken with medications that are strong CYP3A4 inhibitors (i.e. erythromycin, ritonavir) and will significantly decrease if taken with strong CYP3A4 inducers (i.e. efavirenz, rifampin, Saint John's wort). Simeprevir also inhibits intestinal (but not liver) CYP3A. For instance, midazolam, an anticonvulsant, gets metabolized by intestinal CYP3As and taking it with simeprevir can lead to increased midazolam levels that can be toxic. Simeprevir also inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters, which are normally transporters that pump out drug out of the plasma. Thus, taking simeprevir with medications that are substrates for these transporters can lead to increased plasma concentrations of these medications. For example, calcium channel blockers (i.e. diltiazem, amlodipine) are P-gp substrates and can lead to increased concentrations of these drugs when taken with simeprevir. Taking ciclosporin, a substrate for OATP1B1/3, with simeprevir resulted in significant increase in ciclosporin concentration and are therefore not recommended to be taken together.[10][19] WP

Pharmacology

Mechanism of action

Like some other aminocyclopropanes, simeprevir is a hepatitis C virus protease inhibitor.[20] WP

Simeprevir is a NS3/4A protease inhibitor, thus preventing viral maturation through inhibition of protein synthesis. Simeprevir is administered as one capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 or genotype 4 chronic hepatitis C in adult people with compensated liver disease (including cirrhosis), with or without HIV-1 co-infection, who are treatment naive or who have failed previous interferon therapy. Genotype 1 is the most prevalent form of hepatitis C virus (HCV) worldwide.[21][22] WP⚠ Wikipedia itself has flagged this text: citation needed.

Pharmacokinetics

Simeprevir is orally bioavailable. Its absorption increases when taken with food, and is therefore advised to be taken with food. The liver's CYP3A4 enzymes mainly break down simeprevir, but CYP2C8 and CYP2C19 enzymes can also play a role. Its half-life in the plasma is 41 hours in people with HCV. Its peak effect happens 4 to 6 hours after taking the medication. It is primarily excreted into the feces (91%).[10] WP

Chemistry

Formula

C38H47N5O7S2 PC

CAS number

923604-59-5 PC

Molar mass (g/mol)

749.9 PC

IUPAC name (computed by PubChem)

(1R,4R,6S,7Z,15R,17R)-N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide PC

SMILES

CC1=C(C=CC2=C1N=C(C=C2O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(CCCC/C=C\[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)C7=NC(=CS7)C(C)C)OC PC

InChIKey

JTZZSQYMACOLNN-VDWJNHBNSA-N PC

PubChem CID

24873435

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other Simeprevir
2. Other Initial treatment of HCV infection. October 2016
3. Journal / agency Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Alimentary Pharmacology & Therapeutics. June 2016. doi:10.1111/apt.13633 · PMID 27087015
4. Journal / agency Brochot E, Helle F, François C, Castelain S, Capron D, Nguyen-Khac E, Duverlie G. Which therapeutic option for hepatitis C virus genotype 1?. Scandinavian Journal of Gastroenterology. April 2015. doi:10.3109/00365521.2014.978364 · PMID 25396710
5. Other Hamilton R. Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015
6. Other Grubbs RH, O'Leary DJ. Handbook of Metathesis, Volume 2: Applications in Organic Synthesis. 2015
7. Journal / agency Dugum M, O'Shea R. Hepatitis C virus: here comes all-oral treatment. Cleveland Clinic Journal of Medicine. March 2014. doi:10.3949/ccjm.81a.13155 · PMID 24591471
8. Other Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. 2019
9. Other The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). 2019
10. Other OLYSIO (simeprevir) capsules, for oral use FULL PRESCRIBING INFORMATION. September 2014
11. Other Recommendations for Testing, Managing, and Treating Hepatitis C. 2014
12. Other West, Stephen. "Gilead Warns After Hepatitis Patient on Heart Drug Dies". Published 21 March 2015. link 2
13. Journal / agency Highlights of Prescribing Information Copegus. August 2011
14. Other Highlights of Prescribing Information PEGINTRON. July 2014
15. Journal / agency FDA ANTIVIRAL DRUGS ADVISORY COMMITTEE MEETING. October 2013
16. Other Olysio (simeprevir) dosing, indications, interactions, adverse effects, and more
17. Journal / agency Direct-Acting Antivirals for Hepatitis C: Drug Safety Communication - Risk of Hepatitis B Reactivating. 4 October 2016
18. Journal / agency Direct-acting antivirals indicated for treatment of hepatitis C (interferon-free). 17 September 2018
19. Journal / agency Furihata T, Matsumoto S, Fu Z, Tsubota A, Sun Y, Matsumoto S, Kobayashi K, Chiba K. Different interaction profiles of direct-acting anti-hepatitis C virus agents with human organic anion transporting polypeptides. Antimicrobial Agents and Chemotherapy. August 2014. doi:10.1128/AAC.02724-14 · PMID 24867984 · PMC4135986
20. Journal / agency Lin TI, Lenz O, Fanning G, Verbinnen T, Delouvroy F, Scholliers A, Vermeiren K, Rosenquist A, Edlund M, Samuelsson B, Vrang L, de Kock H, Wigerinck P, Raboisson P, Simmen K. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrobial Agents and Chemotherapy. April 2009. doi:10.1128/AAC.01058-08 · PMID 19171797 · PMC2663092
21. Journal / agency European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. Journal of Hepatology. August 2011. doi:10.1016/j.jhep.2011.02.023 · PMID 21371579
22. Journal / agency Zein NN. Clinical significance of hepatitis C virus genotypes. Clinical Microbiology Reviews. April 2000. doi:10.1128/CMR.13.2.223-235.2000 · PMID 10755999 · PMC100152

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.