Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations

Abstract

Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.

Mechanisms of Virologic Failure with Direct-Acting Antivirals in Hepatitis C and Strategies for Retreatment

“…41 The mean area under the curve (AUC) of RBC is fairly similar in patients with ChildPugh class A, B, and C cirrhosis as compared with controls. 38 However, the mean maximum peak plasma drug concentration level values increased with the severity of hepatic dysfunction and were 2 times greater in patients with Child-Pugh class B and C cirrhosis. This finding is evidenced by the close monitoring for side effects, such as anemia, which is recommended with RBV.…”

“…RBV is metabolized in 2 pathways with reversible phosphorylation to monophosphate, diphosphate, and triphosphate metabolites in the nucleated cells and degradation involving deribosylation and amide hydrolysis to a triazole carboxamide. 38 There is no cytochrome P enzyme metabolism associated with RBV.…”

“…The active metabolite is then dephosphorylated to form GS-331007. 38 Because of the lack of metabolism via the CYP enzyme, SOF has no induction or inhibition of CYP enzymes and, thus, has no drug-drug interactions related to the CYP pathway. However, SOF is a substrate of transporter protein Pglycoprotein (pgP) and breast cancer resistance protein.…”

“…A study showed that after 7 days of exposure of SOF, the AUC was 126% and 143% higher in Child-Pugh class B and C, respectively, as compared with patients with normal hepatic function. 38 This finding suggests that, with advancing degrees of portal hypertension, response rates may decline.…”

Discovery of Imidazo[1,2-α][1,8]naphthyridine Derivatives as Potential HCV Entry Inhibitor

“…Overall, it was shown that 5o was orally available and had promising pharmacokinetic properties (T max = 2.17 ± 0.36 h, T 1/2 = 2.93 ± 0.60 h, C max = 2.05 ± 0.26 μM, AUC 0−24h = 18.98 ± 2.49 μM·h). 25 In conclusion, with the known small molecule IFN-like agent RO8191 as lead, we have designed and synthesized a series of imidazo[1,2-α] [1,8]naphthyridine derivatives, some of which exhibited significant anti-HCV activity (EC 50 = 0.02−0.1 μM). Further investigations revealed that these compounds exerted their anti-HCV effect in the viral entry stage, which is distinct from that of RO8191.…”