Simeprevir, sold under the trade names Olysio among others, is a medication used in combination with other medications for the treatment of
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
.
[ It is specifically used for hepatitis C genotype 1 and 4.][ Medications it is used with include ]sofosbuvir
Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken Oral administration, by mouth.
Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are gen ...
or ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
and peginterferon-alfa Peginterferon-alfa may refer to:
* Peginterferon alfa-2a, an antiviral drug used in treatment for hepatitis C and hepatitis B
* Peginterferon alfa-2b, a treatment for hepatitis C
See also
* Interferon
{{Portal bar, medicine} ...
.[ Cure rates are in 80s to 90s percent. It may be used in those who also have ]HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
.[ 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
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
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.][
Simeprevir was developed by Medivir AB and ]Janssen Pharmaceutica
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American ...
. 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
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
in 2019. It is not available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In the United Kingdom a course of treatment with ribavirin and peginterferon-alfa cost about £29,700 in 2015. In the United States a course of treatment with sofosbuvir was more than 171,000 in 2015 with the simeprevir component costing 66,360.
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.
]
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
Viral load, also known as viral burden, is a numerical expression of the quantity of virus in a given volume of fluid, including biological and environmental specimens. It is not to be confused with viral titre or viral titer, which depends on the ...
, 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.][
]
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.
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.][
]
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
Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...
, difficulty breathing and increased bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
. It may reactivate hepatitis B in those who have been previously infected. The European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(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.
Combination treatment
In March 2015, Gilead Sciences
Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
e-mailed warnings to health care providers about nine people that began taking its hepatitis C drugs ledipasvir/sofosbuvir
Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (H ...
or sofosbuvir
Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken Oral administration, by mouth.
Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are gen ...
along with amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...
, daclatasvir
Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depe ...
, or simeprevir developed abnormally slow heartbeats and one died of cardiac arrest
Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
. Three required a pacemaker
An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eith ...
to be inserted. Gilead said the combinations aren't recommended and product labels will be updated.
Mechanism of action
Simeprevir is a hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepato ...
protease inhibitor.
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.
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%).][
]
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."[ People with Q80K polymorphism are not advised to take simeprevir.][
]
Drug interactions
Simeprevir is a CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
substrate so its plasma concentration will significantly increase if taken with medications that are strong CYP3A4 inhibitors (i.e. erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used duri ...
, ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
) and will significantly decrease if taken with strong CYP3A4 inducers (i.e. efavirenz
Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlest ...
, rifampin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...
, Saint John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...
).[
Simeprevir also inhibits intestinal (but not liver) CYP3A. For instance, ]midazolam
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of a ...
, 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 blocker
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s (i.e. diltiazem
Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
, amlodipine
Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth.
Common side effects include swelling, feeling tired, ab ...
) are P-gp substrates and can lead to increased concentrations of these drugs when taken with simeprevir.[ Taking ]ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...
, a substrate for OATP1B1/3, with simeprevir resulted in significant increase in ciclosporin concentration and are therefore not recommended to be taken together.[
]
Approval
In the United States, it is approved by the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) for use in combination with peginterferon-alfa Peginterferon-alfa may refer to:
* Peginterferon alfa-2a, an antiviral drug used in treatment for hepatitis C and hepatitis B
* Peginterferon alfa-2b, a treatment for hepatitis C
See also
* Interferon
{{Portal bar, medicine} ...
and ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
for hepatitis C. Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1.
Clinical study
Simeprevir has been tested in combination regimens with pegylated interferon alfa-2a and ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
, and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir
Daclatasvir, sold under the brand name Daklinza, is an antiviral medication used in combination with other medications to treat hepatitis C (HCV). The other medications used in combination include sofosbuvir, ribavirin, and interferon, vary depe ...
and sofosbuvir
Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken Oral administration, by mouth.
Common side effects include fatigue, headache, nausea, and trouble sleeping. Side effects are gen ...
.Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.
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. 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
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approved direct acting agents, including simeprevir in combination with remdesivir
Remdesivir, sold under the brand name Veklury, Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. is a broad-spectrum antiviral medication developed by the ...
(relevant drug during the Ebola epidemic
This list of Ebola outbreaks records the known occurrences of Ebola virus disease, a highly infectious and acutely lethal viral disease that has afflicted humans and animals primarily in equatorial Africa. The pathogens responsible for the d ...
2014–2016), could be of use in the fight against the global pandemic of Sars-Cov-2. Paritaprevir
Paritaprevir (previously known as ABT-450) is an acylsulfonamide inhibitor of the NS3- 4A serine protease manufactured by Abbott Laboratories that shows promising results as a treatment of hepatitis C. When given in combination with ritonavir ...
, another molecule used to treat Hepatitis type C, also showed promising results in terms of binding energy and stability of the complex formed.
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
In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates ...
.
For SARS-CoV-2, simeprevir acts by inhibiting Main protease (Mpro) and RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
-dependent RNA polymerase
A polymerase is an enzyme ( EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base- ...
, a non-structural protein, essential for viral RNA synthesis.
Mpro belongs to the same enzyme class as NS3/4A, the serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s. It cleaves the translated polyprotein to form proteins elemental to viral transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
and replication. Remdesivir alone only inhibits the polymerase itself; in order to stop viral synthesis, an approved hepatitis C drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
is also administered to stop the spread of the virus.
In vitro, the viral infection of Sars-CoV-2 could be stopped, and in addition it could be observed that further protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s of the virus are inhibited, and the effect of the antiviral
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...
could thus be enhanced. In this regard, clinical studies proving the efficiency on the organism are still lacking at present, which are required before using the drug combination on a large scale as a form of therapy
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
against a Sars-CoV-2 infection.
The hepatitis drugs are considered potential inhibitors of SARS-CoV-2 Mpro in the fight against COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
infection, and the binding affinity and its mechanism, as well as the stability of the complexes formed this way, may serve as a guideline or even template when it comes to designing inhibitors that specifically target this virus. The compounds themselves may also play an important role and shall be studied further in clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s.
References
Further reading
*
External links
*
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