Chemical formula: C₃₈H₄₇N₅O₇S₂ Molecular mass: 749.939 g/mol PubChem compound: 24873435
Simeprevir is a specific inhibitor of the HCV NS3/4A serine protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively.
The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/ml) and 19 nM (14.25 ng/ml), respectively. Chimeric replicons carrying NS3 sequences derived from HCV PI treatment-naïve genotype 1a and genotype 1b patients displayed median fold change (FC) in simeprevir EC50 values of 1.4 (N=78) and 0.4 (N=59) compared to reference genotype 1b replicon, respectively. Genotype 1a and 1b isolates with a baseline Q80K polymorphism resulted in median FC in simeprevir EC50 of 11 (N=33) and 8.4 (N=2), respectively. Median simeprevir FC values against genotype 2 and genotype 3 baseline isolates tested were 25 (N=4) and 1,014 (N=2), respectively. Median simeprevir FC values against baseline isolates of genotype 4a, genotype 4d and genotype 4other were 0.5 (N=38), 0.4 (N=24), and 0.8 (N=29), respectively. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. In vitro combination of simeprevir with interferon, ribavirin, NS5A or NS5B inhibitors resulted in additive or synergistic effects.
Short term monotherapy data of simeprevir from studies C201 (genotype 1) and C202 (genotype 2, 3, 4, 5 and 6) in patients receiving 200 mg once daily simeprevir for 7 days is presented in the following table.
Antiviral activity of simeprevir 200 mg monotherapy (studies C201 and C202):
| Genotype | Mean (SE) change in HCV RNA at day 7/8 (log10 IU/mL) |
|---|---|
| Genotype 1 (N=9) | -4.18 (0.158) |
| Genotype 2 (N=6) | -2.73 (0.71) |
| Genotype 3 (N=8) | -0.04 (0.23) |
| Genotype 4 (N=8) | -3.52 (0.43) |
| Genotype 5 (N=7) | -2.19 (0.39) |
| Genotype 6 (N=8) | -4.35 (0.29) |
The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV infected patients. Plasma exposure of simeprevir (AUC) in HCV infected patients was about 2- to 3-fold higher compared to that observed in healthy subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with peginterferon alfa and ribavirin compared with administration of simeprevir alone.
The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of simeprevir in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose.
In vitro experiments with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.
Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric (928 kcal) and 69% after a normal caloric (533 kcal) breakfast, and delayed the absorption by 1 hour and 1.5 hours, respectively.
Simeprevir must be taken with food. The type of food does not affect exposure to simeprevir.
Simeprevir is extensively bound to plasma proteins (>99.9%), primarily to albumin and, to a lesser extent, alfa-1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Simeprevir is metabolised in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Moderate or strong inhibitors of CYP3A4 significantly increase the plasma exposure of simeprevir, and moderate or strong inducers of CYP3A4 significantly reduce plasma exposure of simeprevir. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.
In vitro experiments show that simeprevir is a substrate for the drug transporters P-glycoprotein (P-gp), MRP2, OATP1B1/3 and OATP2B1. Simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P-gp/MDR1, MRP2, BCRP and BSEP. OATP1B1/3 and MRP2 are involved in the transport of bilirubin into and out of hepatocytes. Simeprevir does not inhibit OCT2 in vitro.
Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (up to 98%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in faeces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in faeces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in faeces accounted for on average 31% of the administered dose.
The terminal elimination half-life of simeprevir was 10 to 13 hours in healthy subjects and 41 hours in HCV infected patients receiving 200 mg simeprevir.
Plasma Cmax and the area under the plasma concentration time curve (AUC) increased more than dose proportional after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once daily dosing.
There is limited data on the use of simeprevir in patients older than 65 years. Age (18-73 years) had no clinically meaningful effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis (n=21, age above 65 years) of HCV infected patients treated with simeprevir. No dose adjustment of simeprevir is required in elderly patients.
Renal elimination of simeprevir is negligible. Therefore, it is not expected that renal impairment will have a clinically relevant effect on the exposure to simeprevir.
Compared to healthy subjects with normal renal function (classified using the Modification of Diet in Renal Disease [MDRD] eGFR formula; eGFR ≥80 ml/min), the mean steady-state AUC of simeprevir was 1.62-fold higher (90% confidence interval: 0.73-3.6) in subjects with severe renal impairment (eGFR below 30 ml/min). As exposure may be increased in HCV infected patients with severe renal impairment, caution is recommended when prescribing simeprevir to these patients.
As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with simeprevir regarding their use in patients with renal impairment.
Simeprevir is primarily metabolised by the liver.
Plasma exposure of simeprevir in HCV infected patients was about 2- to 3-fold higher compared to that observed in healthy subjects.
Compared to healthy subjects with normal hepatic function, the mean steady-state AUC of simeprevir was 2.4-fold higher in non-HCV infected subjects with moderate hepatic impairment (Child-Pugh B) and 5.2-fold higher in non-HCV infected subjects with severe hepatic impairment (Child-Pugh C).
No dose adjustment of simeprevir is necessary in patients with mild hepatic impairment. The safety and efficacy of simeprevir have not been established in HCV infected patients with moderate or severe hepatic impairment (Child-Pugh B or C). Simeprevir is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C).
Refer to the respective Summary of Product Characteristics of the medicinal products used in combination with simeprevir regarding their use in patients with hepatic impairment.
No dose adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin.
No dose adjustment is necessary based on body weight or body mass index. These characteristics have no clinically relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin.
Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian and Black/African American HCV infected patients treated with simeprevir in combination with peginterferon alfa and ribavirin.
In a phase 3 study conducted in China and South-Korea, the mean plasma exposure of simeprevir in Asian HCV infected patients was 2.1-fold higher compared to non-Asian HCV infected patients in a pooled phase 3 population from global studies.
No dose adjustment is necessary based on race.
Pharmacokinetic parameters of simeprevir were comparable between patients with HCV genotype 1 infection with or without HIV-1 co-infection.
The pharmacokinetics of simeprevir in children aged below 18 years have not been investigated.
In rodents, simeprevir elicited toxic effects in the liver, pancreas and gastrointestinal systems. Dosing of animals resulted in similar (dogs) or lower (rats) exposures than those observed in humans at the recommended dose of 150 mg once daily. In dogs, simeprevir was associated with a reversible multifocal hepatocellular necrosis with associated increases in ALT, AST, alkaline phosphatase and/or bilirubin. This effect was observed at higher systemic exposures (11-fold) than those in humans at the recommended dose of 150 mg once daily.
Simeprevir in vitro was very mildly irritating to the eyes. In vitro, simeprevir induced a phototoxic response on BALB/c 3T3 fibroblasts after UVA exposure, in the absence and presence of protein supplements. Simeprevir was not irritating to rabbit skin, and is not likely to cause skin sensitisation.
There were no adverse effects of simeprevir on vital functions (cardiac, respiratory and central nervous system) in animal studies.
Simeprevir was not genotoxic in a series of in vitro and in vivo tests. Carcinogenicity studies with simeprevir have not been conducted.
Studies carried out in rats did not reveal significant findings on fertility, embryo-fetal development or pre- and post-natal development at any of the tested doses (corresponding to a systemic exposure in rats similar or lower than that observed in humans at the recommended dose of 150 mg once daily). Supernumerary ribs and delayed ossification were reported in mice at 4-fold higher exposures than those observed in humans at the recommended dose of 150 mg once daily.
In pregnant rats, simeprevir concentrations in placenta, fetal liver and foetus were lower compared to those observed in blood. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk.
Simeprevir is classified as a PBT (persistent, bioaccumulative and toxic) substance.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
