Simeprevir Sodium
Simeprevir sodium was approved by the Japan Pharmaceuticals Medical Devices Agency (PMDA) on September 27, 2013, then approved by the U.S. Food and Drug Administration (FDA) on November 22, 2013, and approved by European Medicine Agency (EMA) on May 14, 2014. It was co-developed by Johnson & Johnson and Medivir, and marketed as Sovriad® by Johnson & Johnson in Japan.
Simeprevir sodium is a NS3/4A protease inhibitor, thus preventing viral maturation through inhibition of protein synthesis. For use in combination with pegylated interferon (PEG-IFN) and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) patients who are treatment-naive, prior nonresponders or relapsed following treatment with PEG-IFN with or without ribavirin.
Sovriad® is available as capsule for oral use, containing 150 mg of free Simeprevir. The recommended dose is one 150 mg capsule once daily with food.
Update Date：2016-03-08
- Drug Name：
- Simeprevir Sodium
- Research Code：
- TMC-435; TMC-435350
- Trade Name：
- Olysio® / Sovriad®
- MOA：
- NS3/4A protease inhibitor
- Indication：
- HCV infection
- Status：
- Approved
- Company：
- Medivir (Originator), Janssen (Originator), Johnson & Johnson (Originator)
- Sales：
-
$621 Million (Y2015);
$2,302 Million (Y2014);
$23 Million (Y2013); - ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-11-22 | Marketing approval | Olysio | HCV infection | Capsule | Eq. 150mg base | Janssen | Priority |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-05-14 | Marketing approval | Olysio | HCV infection | Capsule | 150 mg | Janssen |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-09-27 | Marketing approval | Sovriad | HCV infection | Capsule | Eq 100 mg Simeprevir | Johnson & Johnson |
Update Date：2015-12-08
|
Molecular Weight | 771.92 | ||||||||||||
| Formula | C38H46N5O7S2•Na | |||||||||||||
| CAS No. | 923604-59-5 (Simeprevir); | |||||||||||||
| Chemical Name | Monosodium(cyclopropylsulfonyl)[(2R ,3aR ,10Z ,11aS ,12aR ,14aR )-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-hexadecahydrocyclopenta [c]cyclopropa[g][1,6]diazacyclotetradecine-12a-carbonyl]azanide | |||||||||||||
| Simeprevir （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-09-02
Update Date：2015-11-25
1. WO2008092955.
Update Date：2016-06-08
Mechanism of Action
Simeprevir is an inhibitor of the HCV NS3/4A protease, which is essential for processing the polyprotein that forms the viral replication complex.
Simeprevir inhibited HCV replication by inhibiting HCV NS3/4A protease of genotype 1a (median Ki = 0.5 nM and IC50 = 2.3 nM) and genotype 1b (Ki = 1.4 nM and IC50 = 5.2 nM).
Simeprevir inhibited the proteolytic activity of 6 out of the 20 cellular enzymes with IC50 <10 μM, but no inhibitory activity in cellular pathway of their enzymes, even at the highest tested concentrations (10 and 300 μM, respectively).
In Vitro Efficacy
Simeprevir inhibited the HCV replicons in replicon cells.
● In Huh7-Luc cell systems for genotype 1b strain Con1b using Luciferase reporter gene-based assay, EC50 = 9.4 nM and EC90 = 19 nM.
● In other cell systems using qRT-PCR-based assay, EC50 = 23-28 nM for 1a and EC50 = 3.7-25 nM for 1b.
● The presence of 50% human serum reduced simeprevir replicon activity by 2.4 folds.
Combination of simeprevir with INF, ribavirin, NA5A inhibitors, and NS5B inhibitors were not significantly antagonistic or synergistic.
Simepreive against clinical HCV isolates with median FC in EC50 = 1.4 for genotype 1a compared to H77 strain, and 0.4 for genotype 1b compared to Con1 strain.
96% (105/109) of the HCV genotype 1 replicons selected under simeprevir expressed NS3 substitutions at F43, Q80, R155, A156, and/or D168, with NS3_D168 mutation being most frequently observed (78%).
● NS3_D168V or A, and R155K mutation displayed large reductions in susceptibility (FC >50).
● NS_Q80K/R, S122R, and D168E displayed lower reductions in susceptibility (FC between 2 and 50).
Update Date：2016-06-08
Absorption of Simeprevir
Exhibited a linear pharmacokinetics in rats following intravenous administration of 5, 10 mg/kg simeprevir, but the increases in Cmax and AUCinf appreared to be greater than dose-proportional at 20 mg/kg simeprevir.
Had a low oral bioavailability in monkeys (18.8%), rabbits (2.5%) and moderate in rats (44%), but high in dogs (73%).
Was absorbed rapidly (Tmax = 1-4 h) in rats, hamsters, rabbits, dogs and monkeys, but slowly in humans (Tmax = 6 h).
Showed a half-life of 8.56 h in humans and 9.9 h in hamsters, which were longer than those in rats (2.6 h), rabbits (3.7 h), monkeys (6.1 h) and dogs (4.2 h), after oral administration.
Had a moderate clearance in rat (1.1-2.31 L/h/kg), hamster (2.26 L/h/kg) and dogs (0.4 L/h/kg), low in monkey (0.25 L/h/kg), but high in rabbit (7.21 L/h/kg), after intravenous administration.
Exhibited a high distribution in rats and rabbits, with an apparent of distribution at 2.77-5.34 L/kg and 40.8 L/kg, but moderate in dogs (0.80 L/kg) and monkeys (0.46 L/kg).
Showed a low permeability, with the Papp(A→B) 0.8 × 10-6 cm/s in Caco-2 cell monolayer model.
Distribution of Simeprevir
Exhibited high plasma protein binding in humans (99.9%), rats (99.8%), mice (99.8%), rabbits (99.8%), monkeys (99.9%) and dogs (99.9%).
Had a Cb:Cp ratio of 0.66 in humans, suggesting that the drug did not well distribute into red blood cells.
In male albino and pigmented rats following a single oral administration:
● The drug was rapidly and well distributed into most tissues, except for the central nervous system since the blood-brain barrier was crossed only by a very small extent.
● Relatively higher drug concentration level was observed in small intestine and liver. The concentrations similar to blood were seen in the spleen, kidneys, lungs and heart. But showed undetectable levels in pigmented tissues (skin, uveal tract, eyeball and brain meninges), compared with blood.
● The radioactivity was below the lower limit of quantitation in most tissues at 24 h post-dose.
Metabolism of Simeprevir
Could be metabolized by a very small extent in liver microsomes and hepatocytes of rats, mice, rabbits, dogs, monkeys and humans.
Overall, the parent drug represented the most abundant component in humans (85%), with M21 as the major metabolite in plasma, but M18 as the main metabolite in rat plasma.
The major metabolism of simeprevir were O-demethylation and oxidation in phaseⅠpathway, and glucuronidation of the
oxidized metabolites in phase Ⅱ.
CYP3A4, CYP3A5 and CYP3A7 were the major metabolizing enzymes, with possible contribution from CYP2C8, 2A6, 2B6 and 2C19.
Excretion of Simeprevir
Was predominantly eliminated in feces in humans (91%), rats (98.7%-99.0%) and dogs (96%), with the parent drug as the most significant component in rats, dogs and humans.
About 17.2% of simeprevir was recovered via biliary excretion in bile duct-cannulated (BDC) rats.
Drug-Drug interaction
Simeprevir was weak inhibitor of CYP2D6 (IC50 = 42.9 μM), CYP2C8 (IC50 = 49.1 μM), CYP2C19 (IC50 = 86.1 μM), CYP3A4 (IC50 ≥40 μM).
Simeprevir did not induce CYP1A2 or CYP3A4 in vitro at 10 μM.
Simeprevir was a substrate of P-gp, BCRP, but had weak inhibition of P-gp (IC50 = 85.9 μg/mL).
Simeprevir was a substrate of OATP1B1, OATP1B3 and OATP2B1, and inhibited OATP1B1 with the percentage of 58%-59% at 25 μM.
Simeprevir was a substrate of MRP2, and inhibited MRP2, BESP and NTCP, with the IC50 of 4.8-14.3, 1.25 and 2.6 μg/mL, respectively.
Update Date：2016-06-08
Single-Dose Toxicity
Single-dose oral administration of simeprevir in mice, rats and monkeys:
● Mouse MTD: >2000 mg/kg
● Rat MTD: >1000 mg/kg
● Monkey MTD: >300 mg/kg
● Major findings included GI tract, liver and heart toxicity.
Repeated-Dose Toxicity
Repeated-dose oral administration of simeprevir in mice, rats, dogs and monkeys from 2 to 39 weeks:
● The major target organs identified as gastrointestinal tract and liver, consistent with the clinical trial safety profile.
● The heart was identified as a potential target organ (acute endocardial and myocardial necrosis) in dogs at high doses (~28-fold of the clinical AUC), yet no cardiac safety signals identified in the clinical trials.
Safety Pharmacology
Simeprevir was evaluated in central nervous system (CNS), respiratory, and cardiovascular studies. Besides, phototoxicity was determined:
● Unexpected drug-related effects occurred on CNS, given that simeprevir was not distributed to the brain.
● 10% to 60% reductions in membrane Na+ current were observed for simeprevir nonspecific partial inhibition.
● Respiratory effects were not observed in dogs or rats.
● A delay in gastric emptying was observed in rats after 1 h following oral doses of simeprevir from 160 mg/kg to 640 mg/kg.
● Phototoxicity was found after exposed to UVA at 5 J/cm2: Photo-Irritancy-Factor (PIF) = 15.917, Mean Phototoxic Effect (MPE) = 0.682.
Genotoxicity
Simeprevir exhibited no mutagenic, clastogenic or aneuploidic activities.
Reproductive and Developmental Toxicity
Fertility and early embryo development: According to FDA reviews, no identified NOAEL; According to PMDA reviews, NOAEL for males and females was 500 mg/kg/day (0.5 × MRHD).
Embryo-fetal Development: The maternal NOAEL was 500 mg/kg/day (3.9 × MRHD) and the developmental NOAEL was <150 mg/kg/day (1.1 × MRHD) in mice. The overall NOAEL was 500 mg/kg/day (0.5 × MRHD) in rats.
Simeprevir was not detected in fetus of pregnant rats, but in lactating neonatal mice.
Carcinogenicity
Carcinogenicity studies were not performed because of the proposed 12-week indication.