Pharmacokinetics of ribavirin in patients with hepatitis C virus.
ABSTRACT A population pharmacokinetic analysis was performed using plasma concentration data (n = 7025) from 380 patients to examine the relationship between ribavirin dose and its pharmacokinetics.
Ribavirin pharmacokinetics were described by a three-compartment model with sequential zero-order and a first-order absorption processes. Interoccasion variability and food effects were included.
Lean body weight (range 41-91 kg) was the only covariate with a clinically significant influence on ribavirin pharmacokinetics, affecting clearance (15.3-23.9 l h(-1)) and the volume of the larger peripheral compartment.
The model provided a good description of the available data, confirmed by accurate estimates of parameter values and low residual variability (17%).
Article: A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection.[show abstract] [hide abstract]
ABSTRACT: We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents.PLoS Computational Biology 01/2012; 8(1):e1002339. · 5.22 Impact Factor
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ABSTRACT: Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.Mayo Clinic Proceedings 10/2011; 86(10):1009-26. · 5.70 Impact Factor
Article: The optimal dose of ribavirin for chronic hepatitis C: From literature evidence to clinical practice: The optimal dose of ribavirin for chronic hepatitis C.[show abstract] [hide abstract]
ABSTRACT: Approximately 170 million people worldwide are chronically infected by hepatitis C virus (HCV), which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. The benchmark therapy for untreated HCV patients is a combination of pegylated interferon-alpha (PEG-IFN) and ribavirin (RBV). Several studies have suggested several potential new approaches to improve HCV therapy-optimization of the dose and duration of RBV therapy, accompanied by careful clinical management, is crucial in ensuring the greatest likelihood of a long response to therapy. RBV causes serious side effects, but in clinical practice, there are no alternatives for the treatment of HCV infection. Based on our results, weight-based doses of RBV are advantageous for genotype 1-infected patients, but its success in genotype 2- and 3-infected patients is unknown, particularly for shorter treatment durations.Hepatitis Monthly 04/2011; 11(4):240-6. · 2.19 Impact Factor