RESUMO
IDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only). IDX375 was well absorbed and well tolerated by all of the study participants. A single-day 200-mg BID dose resulted in exposure-related anti-HCV activity with maximal 0.5 to 1.1 log(10) reductions in plasma HCV RNA. These observations support further clinical investigations of IDX375.
Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C/virologia , Lactamas/farmacologia , Lactamas/farmacocinética , Compostos Organofosforados/farmacologia , Compostos Organofosforados/farmacocinética , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Adulto , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Lactamas/efeitos adversos , Lactamas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/uso terapêutico , RNA Viral/sangue , Carga Viral/efeitos dos fármacosRESUMO
Upregulation of Toll-like receptor 2 (TLR2) plays a critical role in inflammation associated with ischemia/reperfusion-induced tissue damage. OPN-305 is the first humanized IgG4 monoclonal antibody against TLR2 in development and is intended for the prevention of reperfusion injury following renal transplantation and other indications. A phase I, single-center, prospective randomized, double-blind, placebo-controlled study was performed to evaluate single ascending doses of OPN-305 in 41 healthy male subjects (age range: 19-58 years) randomized to OPN-305 or placebo across six cohorts. OPN-305 was well tolerated across all doses, with no elevations in endogenous cytokines. A dose-proportional increase in maximum serum concentration (Cmax) was observed, with area under the curve increasing in a greater-than-dose-proportional manner with increasing elimination half-life. OPN-305 produced full TLR2 receptor blockade on CD14(+)CD45(+) cells (monocytes), from 14 (0.5 mg/kg) to >90 (10 mg/kg) days, with a linear effect on the duration of inhibition of interleukin-6 release after TLR2 stimulation.