Simeprevir (sodium)

Simeprevir (TMC435; TMC435350) sodium is an oral, potent and highly specific hepatitis C virus (HCV) NS3/4A protease inhibitor with a K_i of 0.36 nM. Simeprevir sodium inhibits HCV replication with an EC₅₀ of 7.8 nM. Simeprevir sodium also potently suppresses SARS-CoV-2 replication and synergizes with Remdesivir. Simeprevir sodium inhibits the main protease (M^pro) and the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, and also modulates host immune responses^[1][4]. IC50 & Target: K_i: 0.36 nM (HCV NS3/4A protease)^[1]
EC₅₀: 7.8 nM (HCV replication)^[1]
IC₅₀: 9.6±2.3 μM (SARS-CoV-2 M^pro), 5.5±0.2 μM (SARS-CoV-2 RdRp)^[4] In Vitro: Simeprevir (TMC435) inhibits HCV in a dose-dependent manner in Huh7-Luc cells, with EC₅₀ and EC₉₀ values of 8 nM and 24 nM, respectively^[2].
Simeprevir (TMC435) inhibits NS3/4A proteases from HCV genotypes 1 to 6 with IC₅₀s of 1/0.9/7/30/1.5/2.2/1.6 nM for 1a/1b/2b/3a/4/5/6, respectively^[3].
Simeprevir inhibits SARS-CoV-2 in Vero E6 cells with an IC₅₀ of 9.6±2.3 μM and 5.5±0.2 μM for M^pro and RdRp, respectively^[4]. In Vivo: Simeprevir (TMC435) has moderate terminal elimination half-life (t_1/2=1.5 h and 4.1 h for rat (3 mg/kg, p.o.), monkey (3 mg/kg, p.o.))^[3].
Simeprevir (TMC435350) exhibits a medium-slow rate of absorption, well distribution with the high concentration observed in the liver, and a low clearance^[1].
Pharmacokinetic Parameters of Simeprevir (TMC435350) in male Sprague-Dawley rats^[1].

	IV (2 mg/kg)	PO (10 mg/kg)
CL (L/h/kg)	0.505
Vdss (h)	0.49
AUC0-24 (μM·h)	5.21	2.79
Cmax (μM)		0.73
Tmax (h)		3.0
T1/2 (h)		2.8
F (%)		11
Liver/plasma ratio at 6 h	63.5	32