Simeprevir

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Simeprevir.svg
Systematic (IUPAC) name
(2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2-{[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy}-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide
Clinical data
Pronunciation sim-E-pre-vir
Trade names Olysio, Sovriad, Galexos
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral (capsules)
Pharmacokinetic data
Bioavailability 62% (under fed conditions)
Protein binding >99.9%
Metabolism Hepatic (CYP3A, CYP2C8, CYP2C19)
Biological half-life 10–13 hours (HCV-uninfected subjects), 41 hours (HCV-infected subjects)
Excretion Feces (91%), urine (<1%)
Identifiers
CAS Number 923604-59-5
ATC code J05AE14 (WHO)
PubChem CID: 56928193
IUPHAR/BPS 7367
DrugBank DB06290
ChemSpider 23331536
UNII 9WS5RD66HZ
KEGG D10081
ChEMBL CHEMBL501849
NIAID ChemDB 489101
Synonyms TMC435; TMC435350
Chemical data
Formula C38H47N5O7S2
Molecular mass 749.94 g/mol
  • Cc1c(ccc2c1nc(cc2O[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)c7nc(cs7)C(C)C)OC
  • InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24-,27-,28-,38-/m1/s1
  • Key:JTZZSQYMACOLNN-VDWJNHBNSA-N

Simeprevir (formerly TMC435; trade names Olysio and Sovriad) is a drug for the treatment and cure of hepatitis C.[1] It was developed by Medivir and Johnson & Johnson's pharmaceutical division Janssen Pharmaceutica. In the United States, simeprevir is approved by the Food and Drug Administration for use in combination with peginterferon-alfa and ribavirin for hepatitis C.[2] Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1.[3]

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).[4] It is primarily efficacious in treating Hepatitis C virus (HCV) genotype 1 infected subjects with compensated liver disease, including cirrhosis.[4] There are currently no studies that show Simeprevir’s effectiveness as a single therapy for HCV.[4] Simeprevir is generally used for HCV genotype 1 infected subjects, but off-label medical use has been indicated for type 4 genotype as well.[5]

Dosing

Simeprevir is dosed along with peg-IFN and RBV as triple therapy.[4] Appropriate dosing of Simeprevir is dependent upon the patient’s liver function, kidney function, viral load, HCV genotype.[4] This medication is not recommended for patients with moderate or severe liver impairment and patients with end-stage kidney disease since Simprevir was not studied for use in these patient populations.[4] Simeprevir might be discontinued depending on their viral load.[4] 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.[4]

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, patients with sickle cell anemia are contraindicated to RBV therapy and are therefore contraindicated to simeprevir and peg-IFN joint therapy.[6] Pregnant women and men whose female partners are pregnant are contraindicated for simeprevir since peg-IFN and RBV are known to cause birth defects.[4][6][7]

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.[4][6][7] RBV has been shown to cause birth defects and fetal deaths in animal studies.[6] Peg-IFN has been shown to cause abortions in animal studies.[7] Patients must have a negative pregnancy test prior to starting therapy, use at least two effective contraception methods during treatment, and undergo monthly pregnancy tests.[4] If pregnant patients are exposed to any medication regimen containing ribavirin, they are encouraged to report this through the ribavirin pregnancy registry.[6]

Mechanism of action

Simeprevir is a hepatitis C virus protease inhibitor.[8]

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 patients with compensated liver disease (including cirrhosis), with or without HIV-1 co-infection, who are treatment naive or who have failed previous interferon therapy.[9][10] 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.[4] The liver's CYP3A4 enzymes mainly break down simeprevir, but CYP2C8 and CYP2C19 enzymes can also play a role.[4] Its half-life in the plasma is 41 hours in HCV patients.[4] Its peak effect happens 4–6 hours after taking the medication.[4] It is primarily excreted into the feces (91%).[4]

Pharmacogenomics

According to simeprevir's prescriber information, its efficacy in combination with peginterferon alfa and ribavirin is "substantially reduced in patients with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with HCV genotype 1a without Q80K polymorphism."[4] Patients with Q80K polymorphism are not advised to take simeprevir.[4]

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).[4] 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.[4] Simeprevir also inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters, which are normally transporters that pump out drug out of the plasma.[4][11] 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.[4] 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.[4]

Adverse effects

Pruritis (22%), photosensitivity (5%), and rash (25%) are some of the common adverse effects of Simeprevir experienced by patients taking it during Phase 3 trials [12]

Hepatitis C Treatment Combination Dangers

In March 2015, Gilead Sciences e-mailed warnings to health care providers about nine patients that began taking its hepatitis C drugs Harvoni (ledipasvir/sofosbuvir) or Sovaldi (sofosbuvir) along with the heart treatments amiodarone, Bristol-Myers Squibb's Daklinza (daclatasvir), or Johnson & Johnson's Olysio (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.[13]

Clinical study

Simeprevir has been tested in combination regimens with pegylated interferon alfa-2a and ribavirin,[14] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir[15] and sofosbuvir.[16]

Results from three phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1 were favourable and resulted in FDA supporting the approval of simeprevir for Hepatitis C genotype 1.[17] Interestingly, members of the FDA commented following a presentation by Johnson & Johnson (24 October 2013) that post-marketing studies in racial and ethnic minorities, patients co-infected with HIV, and other underrepresented populations is needed.

In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions. A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment. Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).

A recent study has shown effectiveness of simepivir therapy with PEG-INF and RBV in post-liver transplant patients with recurrent Hepatitis C.[18]

References

  1. ↑ News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 7.2 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ West, Stephen. "Gilead Warns After Hepatitis Patient on Heart Drug Dies". Published 21 March 2015.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
  16. ↑ 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.
  17. ↑ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM371623.pdf
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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