Simeprevir

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.[2][3][4] It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

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.[5] Simeprevir is a HCV protease inhibitor.[5]

Simeprevir was developed by Medivir AB and Janssen Pharmaceutica.[6] It was approved for medical use in the United States in 2013.[7] It was removed from the World Health Organization's List of Essential Medicines in 2019.[8][9] It is not available as a generic medication as of 2015.[10]

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).[11] It is primarily effective in treating Hepatitis C virus (HCV) genotype 1 infected subjects with compensated liver disease, including cirrhosis.[11] There are currently no studies that show Simeprevir's effectiveness as a single therapy for HCV.[11] Simeprevir is generally used for HCV genotype 1 infected subjects, but off-label medical use has been indicated for type 4 genotype as well.[12]

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.[13] Pregnant women and men whose female partners are pregnant are contraindicated for simeprevir since peg-IFN and RBV are known to cause birth defects.[11][13][14]

Adverse effects

Severe itching (22%), sensitivity to sunlight (5%), and rash (25%) are some of the common adverse effects of simeprevir.[15] Other side effects may include nausea, muscle pain, difficulty breathing and increased bilirubin.[16] It may reactivate hepatitis B in those who have been previously infected.[17] 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.[18]

Mechanism of action

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

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.[21][22] Genotype 1 is the most prevalent form of hepatitis C virus (HCV) worldwide.

Pharmacokinetics

Simeprevir is orally bioavailable. Its absorption increases when taken with food, and is therefore advised to be taken with food.[11] The liver's CYP3A4 enzymes mainly break down simeprevir, but CYP2C8 and CYP2C19 enzymes can also play a role.[11] Its half-life in the plasma is 41 hours in people with HCV.[11] Its peak effect happens 4 to 6 hours after taking the medication.[11] It is primarily excreted into the feces (91%).[11]

Pharmacogenomics

According to simeprevir's prescriber information, its efficacy in combination with peginterferon alfa and ribavirin is "substantially reduced in people with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to people infected with HCV genotype 1a without Q80K polymorphism."[11] People with Q80K polymorphism are not advised to take simeprevir.[11]

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).[11] 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.[11] Simeprevir also inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters, which are normally transporters that pump out drug out of the plasma.[11][23] 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.

Approval

In the United States, it is approved by the Food and Drug Administration (FDA) for use in combination with peginterferon-alfa and ribavirin for hepatitis C.[24] Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1.[25]

Clinical study

Simeprevir has been tested in combination regimens with pegylated interferon alfa-2a and ribavirin,[26] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir[27] and sofosbuvir.[28]

Results from three phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in people with chronic HCV GT1 were favourable and resulted in FDA supporting the approval of simeprevir for Hepatitis C genotype 1.[15] Members of the FDA commented following a presentation by Johnson & Johnson (24 October 2013) that post-marketing studies in racial and ethnic minorities, people co-infected with HIV, and other underrepresented populations are needed.

SARS-CoV-2 research

Several studies have been testing if the virostatic mechanism of FDA approved direct acting agents, including simeprevir in combination with remdesivir (relevant drug during the Ebola epidemic 2014–2016), could be of use in the fight against the global pandemic of Sars-Cov-2. Paritaprevir, another molecule used to treat Hepatitis type C, also showed promising results in terms of binding energy and stability of the complex formed.[29]

The advantage of working with such compounds is that they are already FDA approved antivirals, which means that clinical trial phases can be initiated more quickly. The speed of medical response is a critical factor influencing the global consequences of the pandemic; the faster antidotes such as drugs and/ or vaccines are available on a large scale, the more promising is the containment of the disease and its (economic) consequences. Speed is a crucial factor, especially regarding the fight of viruses, which by nature have an extremely high mutation rate.

For SARS-CoV-2, simeprevir acts by inhibiting Main protease (Mpro) and RNA-dependent RNA polymerase, a non-structural protein, essential for viral RNA synthesis.[29]

Mpro belongs to the same enzyme class as NS3/4A, the

Further reading

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