Chronic hepatitis C virus (HCV) infection afflicts an estimated 71 million individuals worldwide and leads to significant morbidity and mortality, including liver cirrhosis and hepatocellular carcinoma. HCV is comprised of six main genotypes and 86 known subtypes. Further, within these subtypes there are multiple resistance associated substitutions (RAS, plural RASs) in the HCV genome measurable at baseline or appearing during or after treatment[4]. Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons[5]. The replicon EC50 values (effective concentration to inhibit viral replication by 50%) for velpatasvir, GT(EC50 value): 1a (14 pM); 1b (16 pM); 2a JFH1 (8 pM); 2a J6 (16 pM); 2b (6 pM); 3a (4 pM); 4a (9 pM); 5a (54 pM); 6a (6 pM); 6e (130 pM)[4]. In human liver microsomes, velpatasvir shows no measureable disappearance of parent during a 60 min incubation, leading to a Pred CL < 0.16 L/h/kg. In cryopreserved human he-patocytes 3H-velpatasvir undergoes minimal metabolism and the Pred CL is exceedingly low at 0.06 L/h/kg (4.7% hepatic extraction, Eh%)[4]. The percent free drug in plasma measured by dialysis is similar across species ranging from 0.2 to 0.4% free for rat, dog and cyno; human is within this range at 0.3% free. The steady-state volume of distribution (Vss) is similar across the preclinical species and is larger than total body water ranging from 1.4 to 1.6 L/kg. The half-lives of velpatasvir are 2.3, 5.2 and 5.0h in rat, dog and cyno respectively[4].
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