Simeprevir

Absorption

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir capsule in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours following the oral administration.

Toxicity

In a combination therapy with sofosbuvir, most common reported adverse effects is fatigue, headache and nausea. In case of triple therapy with PEG-Interferon Alfa-2A and ribavirin, most common adverse effects included rash (including photosensitivity), pruritus and nausea. Elevations of serum bilirubin may be observed due to inhibition of bilirubin transporters OATP1B1 and MRP2 by simeprevir.

Description

In September 2013, simeprevir (also known as TMC435) was approved in Japan (trade name Sovriad?) for the treatment of genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). Simeprevir was approved for the same indication in November 2013 in the United States (trade name Olysio?) and Canada (trade name Galexos?). Simeprevir is the third HCV PI to receive approval and was discovered from an effort to optimize a novel series of cyclopentane-core macrocyclic HCV PIs. Unlike the earlier PIs, simeprevir does not rely on formation of a covalent intermediate to inhibit the enzyme, but instead gains binding affinity through a large P2 quinoline substituent that occupies an extended S2 subsite of HCV protease by induced fit. This pocket is not occupied by inhibitors such as telaprevir and boceprevir. Other key features of simeprevir are truncation of the P3 capping group (the N-methyl amide), use of an acylsulfonamide as an acid isostere, and incorporation of an isopropylthiazole group to give improved permeability. Simeprevir is a potent NS3/4A PI (Ki=0.36 nM), with antiviral activity in the HCV replicon assay (genotype 1b EC₅₀=7.8 nM; genotype 1a EC₅₀=28.4 nM). It is 25-fold less potent against HCV genotype 2, >1000 less potent for HCV genotype 3, but has 3-fold better potency for HCV genotype 4.

Originator

Tibotec and Medivir (Ireland and Sweden)

The Uses of Simeprevir

Simeprevir-d3 is labelled Simeprevir (S466500) which is a hepatitis C virus (NS3/4A) protease inhibitor. Simeprevir (S466500) is used for the cure and treatment of hepatitis C.

Background

Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated in patient's with HCV genotype 1 for the treatment of chronic hepatitis C virus (HCV) infection. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . Like all NS3/4A inhibitors, simeprevir is a serine protease inhibitor in similarity to Boceprevir and Telaprevir but is classified as a second generation protease inhibitor. This class of antiviral drugs were the first direct acting antivirals approved but are associated with lower cure rates than newer drugs. Broad use of simeprevir occurred when it was used in combination with a newer drug, Sofosbuvir. Inhibiting HCV NS3/4A protease in a potent and highly specific manner, simeprevir is a direct-acting antiviral agent against the hepatitis C virus. Since the viral protease NS3/4A complex is essential for cleaving the HCV encoded polyprotein into individual viral proteins facilitating replication , the drug blocks the viral replication process. It is shown to display synergistic effects with interferon-α and HCV NS5B inhibitor, and additive effects with ribavirin in HCV replicon cells . Unlike first generation serine protease inhibitors, simprevir has a sightly different resistance profile where limited therapeutic efficacy of the drug is observed with NS3 Q80K polymorphic variants and simeprevir-specific amino acid position of 168 also results in higher treatment failure rates . The observed prevalence of the N3 Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b .
According to 2017 American Association for the Study of Liver Diseases (AASLD) and 2015 consensus guidelines from the Canadian Association for the Study of the Liver (CASL), simeprevir can be used as first-line or second-line threapies for treatment-na?ve patients as adjunct to sofosbuvir treatment for genotype 1 or PEG-Interferon/ribavirin combination therapy for genotype 1 or 4. The combination therapy of simeprevir and other antiviral agents are initiated in HCV-positive patients with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .
Simeprevir was approved by the FDA in November 2014 and is marketed under the brand name Olysio as oral tablets. Administered once daily with food, 150mg simeprevir capsule is used in combination with Sofosbuvir in patients with HCV genotype 1 without cirrhosis for 12 week duration. In patients with HCV genotype 1 with compensated cirrhosis, the treatment is directed for 24 week duration. Sustained virologic response 12 weeks after planned end of treatment (SVR12) was achieved in 170/176 (97%) subjects without cirrhosis treated with 12 weeks simeprevir in combination with sofosbuvir (FDA Label). The overall SVR12 was 88% (44/50) in treatment-na?ve patients with cirrhosis .
Simeprevir is also used in treatment of HCV genotype 4 patients with or without cirrhosis and is taken with Peginterferon alfa-2a and Ribavirin; this triple therapy allows shortening treatment duration from 48 weeks or longer to 12 or 24 weeks depending on prior response status and presence of HIV-1 co-infection. Prior to initiation of treatment with Peginterferon alfa-2a and Ribavirin, screening for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and if detected, alternative treatment should be considered instead to prevent therapeutic failure. The SVR12 was 83% (29/35) in treatment-na?ve patients and 86% (19/22) in relapsing patients.

Indications

Indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection: typically in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis and in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.
Resistance: Reduced susceptibility to simeprevir was most commonly associated with the viral NS3 Q80K polymorphism. Amino acid substitutions at NS3 positions S122, R155 and/or D168 are also shown to reduce susceptibility to simeprevir in genotype 1a/b patients.

What are the applications of Application

Simeprevir is Simeprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor

Definition

ChEBI: Simeprevir is an azamacrocycle and a lactam.

brand name

Sovriad

Pharmacokinetics

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 .

Clinical Use

HCV NS3/4A serine protease inhibitor:
Treatment of hepatitis C in combination with other treatment

Synthesis

Commercial 2-methyl-3-methoxybenzoic acid (153) was treated with diphenylphosphorylazide (DPPA) and triethylamine to affect a Curtius rearrangement and the resulting isocyanate was trapped with t-butanol to produce the Boc-protected aniline 154 in quantitative yield. Upon removal of the Boc protecting group with TFA, the resulting aniline was reacted with boron trichloride followed by the addition of acetonitrile and aluminum trichloride to affect Friedel¨CCrafts acylation to give aminoacetophenone 155 in 40% yield. Acylation of the amino group with 4-isopropylthiazole- 2-carbonyl chloride (156) gave ketoamide 157 in 90% yield, which was treated with potassium tert-butoxide in t-butanol at 100 ?? to furnish quinolinol 158 in 88% yield.
Use of a ring closing metathesis approach, enabling the synthesis of the macrocyclic portion of the drug and ultimately simeprevir, is described. Hydrogenation of commercial trans-cyclopentanone-3,4-dicarboxylic acid (159) over Raney Ni in the presence of triethylamine followed by cyclization to the lactone using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM), and subsequent cinchonidine salt formation gave lactone acid 160 in 26% yield over the 3 steps in 97% ee. Next, amide coupling with N-methylhexenylamine using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), Fischer esterification, and subsequent introduction of the quinolinol fragment 158 under Mitsunobu conditions using triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) provided methyl ester 161 in 65% overall yield for the three steps. Saponification of the ester with lithium hydroxide followed by EEDQ-promoted coupling to (1R,2S)-1-amino-2-vinyl-cyclopropane ethyl ester (162) and Boc protection of the resulting amide gave the RCM substrate, diene 163 in 95% yield for the two steps. Macrocyclization of 163 using the second generation M2 catalyst under dilute concentration in refluxing toluene followed by acidic removal of the amide protecting group gave cycloalkene ester 164 in high yield. Saponification of the ester, activation of the resulting acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and coupling with cyclopropylsulfonamide led to simeprevir (XXI) in high overall yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of bradycardia with amiodarone.
Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration of both drugs increased with erythromycin - avoid; concentration reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - avoid.
Antivirals: concentration of both drugs increased with darunavir - avoid; concentration reduced by efavirenz; avoid with etravirine; concentration possibly reduced by nevirapine - avoid; concentration increased by ritonavir - avoid.
Ciclosporin: avoid concomitant use, increased simeprevir concentration.
Cobicistat: concentration possibly increased by cobicistat - avoid.

Metabolism

Simeprevir undergoes hepatic metabolism. The primary metabolic pathway involves CYP3A system-mediated oxidation. Involvement of CYP2C8 and CYP2C19 cannot be excluded.

Metabolism

Hepatically metabolised. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system.
Elimination of simeprevir occurs via biliary excretion. Following a single oral administration of 200 mg [14C]-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in faeces. Unchanged simeprevir in faeces accounted for on average 31% of the administered dose. Renal clearance plays an insignificant role in its elimination.