ASV has shown activity against HCV GT1 and 4 in combination with Peg-IFN/RBV, or as part of all-oral DAA combinations in current ongoing Phase III clinical trials 11, 12, 13. A drug-drug interaction (DDI) study in healthy subjects has suggested that coadministration of ASV and DCV does not result in a clinically meaningful pharmacokinetic (PK) interaction. Daclatasvir (BMS790052, DCV) is a first-in-class, highly selective NS5A replication complex inhibitor, which is rapidly absorbed with a t max of 1–2 h and is mainly metabolized by hepatic CYP3A4 and excreted in fecal matter, with an elimination t 1/2 of 13–15 h 9, 10. A combination of DAA therapy, which has a good safety profile and does not include IFN or RBV that lack cross-resistance, will probably be the new recommended regimen and may possibly eradicate HCV worldwide in the near future 7.Īsunaprevir (BMS650032, ASV) is a selective NS3 protease inhibitor that is rapidly absorbed over time and subsequently reaches a maximum plasma concentration ( t max) of 2–4 h and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and fecal excretion, with an elimination half-life ( t 1/2) of 15–20 h 8. The current approved IFN-based regimen and Peg-IFN- and RBV-free (PR-free) regimen show high potency, favorable tolerability profile, a higher barrier to resistance, shorter treatment duration, all-oral regimen, pan-genotypic character, fewer drug interactions and a decreased pill burden, as compared with the previous standard treatment 7. Recently, novel direct-acting antiviral agents (DAAs) have been developed to target specific nonstructural proteins in the HCV life cycle, including NS3/4A protease inhibitors, NS5A protein inhibitors, and NS5B polymerase inhibitors 6. However, fewer than 50% of patients infected with HCV genotype 1 (GT1, the most prevalent and difficult-to-cure genotype in the western world) treated with SOC achieve successful HCV treatment outcomes, ie, sustained virological response (SVR) 3, 4, 5. For the past two decades, until 2011, PEGylated interferon-α (Peg-IFN-α) in combination with ribavirin (RBV) was recommended as a standard-of-care (SOC) treatment for chronic hepatitis C 2. More than 185 million people globally have been estimated to be chronically infected with the hepatitis C virus (HCV), which is one of the leading causes of cirrhosis and liver failure 1. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs. Both the rates were in general agreement. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. An empirical exponential function revealed that IC 50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. A sigmoid E max function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. The IC 50 values of DCV and ASV were estimated to be 0.041 and 2.45 μg/L, respectively, in GT1A patients. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection.
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