TMC435350 (Simeprevir) is an oral HCV NS3/4A protease inhibitor. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC(50)) of 8 nM and a selectivity index of 5,875. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. Data from phase I and II clinical trials of TMC-435350 (Simeprevir) have shown that TMC435350 is well tolerated as a once-daily oral therapy and provides potent antiviral activity in HCV genotype 1-infected subjects, with restoration of liver enzymes and no evidence of viral breakthrough.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
Molecular modeling study on the resistance mechanism of HCV NS3/4A serine protease mutants R155K, A156V and D168A to TMC435.
Xue W, et al. Antiviral Res. 2012 Jan;93(1):126-37. PMID: 22127068.
Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial.
Manns M, et al. Antivir Ther. 2011;16(7):1021-33. PMID: 22024518.
In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.
Lin TI, et al. Antimicrob Agents Chemother. 2009 Apr;53(4):1377-85. PMID: 19171797.
Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
Raboisson P, et al. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. PMID: 18678486.
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