Drug information of Simeprevir

Mechanism of effect

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.

Pharmacodynamic

Simeprevir is a direct-acting antiviral agent and inhibitor for HCV NS3/4A protease, which is an important enzyme required for viral replication. Unlike Boceprevir and Telaprevir, simeprevir is a competitive, reversible, macrocyclic, noncovalent inhibitor. The macromolecular cyclic portion of the molecule improves the affnity and selectivity characteristics, which allows rapid association and slow dissociation to the protein target through noncovalent binding.

Pharmacokinetics

Food increases systemic exposure by 60-70%

Peak plasma time: 4-6 hr

Predose plasma concentration: 1936 ng/mL

AUC: 57,469 ng•hr/mL

Protein bound: >99.9%

Metabolism:

Substrate: CYP3A (major); CYP2C8 (minor) and CYP2C19 (minor)

Inhibits OATP1B1/3 and P-gp transporters

Mildly inhibits CYP1A2 and intestinal CYP3A, but does not affect hepatic CYP3A4 activity

Half-life: 41 hr (HC- infected); 10-13 hr (HCV-uninfected)

Excretion: Hepatobiliary; 91% feces (31% unchanged); <1% urine

Pharmacogenomics

Efficacy is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline; screening patients for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended

Simeprevir exposures are higher in populations with lower amounts of CYP3A and/or OATP1B1/3 including patients of East Asian ancestry

IL28B genetic variant

• A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon alfa and ribavirin
• Overall, sustained viral response rates were lower in subjects with the CT and TT genotypes compared to those with the CC genotype

Dosage

Adult

150 mg orally once a day with food

Pediatric

Safety and efficacy not established

Drug contraindications

Hypersensitivity

Side effects

nausea , myalgia , itching , Photosensitivity , shortness of breath , Rash

Interactions

Eluxadoline , Tipranavir , Erythromycin , Oxecarbazepin , Itraconazole , Posaconazole , Tenofovir , Diltiazem , Delavirdine , Edoxaban , Elvitegravir , st. john's wort , Venetoclax , Indinavir , Idelalisib , Efavirenz , EMTRICITABINE , aminolevulinic acid oral , cobicistat , Rifapentine , ritonavir , saquinavir , nelfinavir , nevirapine , Fosamprenavir , Voriconazole , Carbamazepine , Ketoconazole , Clarithromycin , ledipasvir and sofosbuvir , Rifabutin , Rifampin , Cisapride , Cyclosporine , Fluconazole , Phenobarbital , Phenytoin , Etravirine , Mibefradil , Aminolevulinic acid topical , Cabozantinib , Cariprazine , Cobimetinib , Temsirolimus , ELBASVIR/GRAZOPREVIR , oleandomycin , voxelotor , tucatinib

Alerts

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

Serious symptomatic bradycardia in patients taking amiodarone with sofosbuvir in combination with simeprevir reported, especially in patients receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease; coadministration of amiodarone with simeprever in combination with sofosbuvir not recommended; in patients without alternative treatment options, cardiac monitoring is recommended

Hepatic decompensation and hepatic failure, including fatal cases, reported when coadministered with peginterferon alfa and ribavirin or in combination with sofosbuvir; most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure; monitor liver chemistry tests before and during simeprevir combination therapy

Photosensitivity reported, including serious reactions which resulted in hospitalization

Rash may occur, most frequently within the first 4 weeks; mild-to-moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (eg, oral lesions, conjunctivitis) or systemic symptoms; discontinue if rash becomes severe

Contains a sulfonamide moiety; in subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions was observed; however, insufficient data exist

Must NOT be used as monotherapy

Drug interaction overview

• Avoid coadministering with moderate or strong CYP3A inhibitors; simeprevir AUC increased >7-fold
• Avoid coadministering with moderate or strong CYP3A inducers; simeprevir trough levels decreased >90%

Black Box Warnings

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs and were not receiving HBV antiviral therapy

Some cases have resulted in fulminant hepatitis, hepatic failure, and death

Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up

Initiate appropriate patient management for HBV infection as clinically indicated

Points of recommendation

• If you have a sulfa (sulfonamide) allergy, talk with your doctor.
• If you are of East Asian descent, talk with your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Very bad skin reactions to sunlight have happened with simeprevir. Sometimes, this has led to need to go to the hospital. Talk with the doctor.
• Slow heartbeat and the need to get a pacemaker have happened when amiodarone was given with sofosbuvir and certain other hepatitis C drugs. Sometimes, this has been deadly. Slow heartbeat has happened up to 2 weeks after starting hepatitis C treatment. You will need to be watched closely if you will be taking amiodarone with hepatitis C treatment. Follow what your doctor has told you to do. Call your doctor right away if you have signs of slow heartbeat like chest pain, confusion, dizziness, passing out or near-passing out, memory problems, shortness of breath, tiredness, or weakness.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• If you stop taking any of your other drugs to treat hepatitis C, talk with your doctor. You may need to stop taking simeprevir also.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking simeprevir with your other drugs.
• Use birth control that you can trust to prevent pregnancy while taking simeprevir.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using simeprevir while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• Take simeprevir with food.
• Swallow whole. Do not chew, open, or crush.
• Take simeprevir at the same time of day.
• Keep taking simeprevir as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of simeprevir during treatment.

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Pregnancy level

Not assigned

Related drugs

paritaprevir , boceprevir , Telaprevir