Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function

Kamar, Nassim; Chatelut, Étienne; Manolis, Efthymios; Lafont, Thierry; Izopet, Jacques; Rostaing, Lionel

doi:10.1053/j.ajkd.2003.09.019

Cited by 75 publications

(60 citation statements)

References 22 publications

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“…This study and the resulting model provide a framework for integrating cumulative knowledge of relationships between ribavirin dosing, systemic and intracellular kinetics, ribavirin-induced anemia, and HCV kinetics to achieve higher sustained virological response rates with less-hemolytic anemia. Consistent with previous reports (10,24,25), we found that a linear two-compartment pharmacokinetic model with first-order absorption described ribavirin plasma concentration-time profiles following oral administration in the study population. The estimates for the apparent volumes of distribution for V c /F of 756 liters and V p /F of 3,460 liters correspond to an apparent volume of distribution at the steady state of 4,216 liters, which is within the range of reported values of 2,000 to 5,000 liters (10,26).…”

Section: Discussionsupporting

confidence: 80%

Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

Rower

Burton

et al. 2015

Antimicrob Agents Chemother

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e Ribavirin, a guanosine analog, is a broad-spectrum antiviral agent. Ribavirin has been a fundamental component of the treatment of hepatitis C virus (HCV) infection for decades, but there is a very limited understanding of the clinical pharmacology of this drug. Furthermore, it is associated with a major dose-limiting toxicity, hemolytic anemia. Ribavirin undergoes intracellular phosphorylation by host enzymes to ribavirin monophosphate (RMP), ribavirin diphosphate (RDP), and ribavirin triphosphate (RTP). The intracellular forms have been associated with antiviral and toxic effects in vitro, but the kinetics of these phosphorylated moieties have not been fully elucidated in vivo. We developed a model to characterize the plasma pharmacokinetics of ribavirin and the difference between intracellular phosphorylation kinetics in red cells (nonnucleated) and in peripheral blood mononuclear cells (nucleated). A time-independent two-compartment model with first-order absorption described the plasma data well. The cellular phosphorylation kinetics was described by a one-compartment model for RMP, with the formation rate driven by plasma concentrations and the first-order degradation rate. RDP and RTP rapidly reached equilibrium with RMP. Concomitant telaprevir use, inosine triphosphatase genetics, creatinine clearance, weight, and sex were significant covariates. The terminal ribavirin half-life in plasma and phosphorylated anabolites in cells was approximately 224 h. We found no evidence of time-dependent kinetics. These data provide a foundation for uncovering concentration-effect associations for ribavirin and determining the optimal dose and duration of this drug for use in combination with newer direct-acting HCV agents. (This study has been registered at ClinicalTrials.gov under registration no. NCT01097395.) R ibavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a nucleoside analog first synthesized in 1972, exhibits broad-spectrum antiviral activity against several RNA and DNA viruses in vitro (1, 2). For several decades, ribavirin was combined with pegylated interferon alpha (Peg-IFN-␣) as the standard of care for treating chronic hepatitis C virus (HCV) infections. Though several directacting antiviral agents have recently been approved for the treatment of HCV and dozens more are in various stages of clinical development, ribavirin remains an important component of several HCV treatment regimens (3-7).Ribavirin's mechanism of antiviral action is not completely understood. In vitro, ribavirin has been shown to mimic the endogenous nucleoside guanosine, and its triphosphate anabolite (ribavirin triphosphate [RTP]) may be incorporated into replicating RNA strands by viral RNA polymerases. This erroneous incorporation inhibits chain elongation and viral replication. Other antiviral effects observed in vitro include immunologic modulation through switching the T-cell phenotype from phenotype 2 to phenotype 1, inhibition of host IMP dehydrogenase leading to depletion of intracellular GTP pools, induction o...

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Section: Discussionsupporting

confidence: 80%

Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

Rower

Burton

et al. 2015

Antimicrob Agents Chemother

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“…Body weight was found to have a significant impact on both CL/F and Vp/F, which was also consistent with previous reports (22)(23)(24)(25). Using a constant infusion model during 4 weeks of treatment, Jen et al reported that CL/F was dependent on body weight, age, gender, and serum creatinine (22).…”

Section: Discussionsupporting

confidence: 80%

“…Using a constant infusion model during 4 weeks of treatment, Jen et al reported that CL/F was dependent on body weight, age, gender, and serum creatinine (22). Two other population PK analyses included patients with mild to severe renal impairment, where CRCL had a significant impact on ribavirin CL/F (24,25). Utilizing a threecompartment model with a sequential zero-order and firstorder absorption, Wade et al reported that lean body weight was the only covariate that had a significant effect on both CL/F and Vp/F at steady state (23).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection

Jin

Fossler

McHutchison

et al. 2012

AAPS J

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Abstract. We report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n=71 African American (AA) and n=73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a twocompartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC 0−7 ). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.

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“…In patients with GFR less than 30 ml/min the blood area under the curve of RBV is threefold higher than in those with normal renal function. Thus, daily dosage of RBV in patients with chronic kidney disease should be adapted to GFR value and predicted according to specific formulas (129,130). RBV is not removed by hemodialysis (131).…”

Section: Ribavirin (Rbv)mentioning

confidence: 99%

Hepatitis C Infection and Chronic Renal Diseases

Perico¹,

Cattaneo²,

Bikbov³

et al. 2009

Clinical Journal of the American Society of Nephrology

189

164

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More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for over 1 million deaths resulting from cirrhosis and liver cancers. Extrahepatic manifestations are also relevant and include mixed cryoglobulinemia, lymphoproliferative disorders, and kidney disease. HCV infection is both a cause and a complication of chronic kidney disease, occurring largely in the context of mixed cryoglobulinemia. This infection also represents a major medical and epidemiologic challenge in patients with end-stage renal disease on renal replacement therapy with dialysis or transplantation. In these settings the presence of HCV correlates with higher rates of patient mortality than in HCV-negative subjects on dialysis or undergoing kidney transplant. The major concern is the lack of safe and effective drugs to treat HCV-infected patients with chronic kidney disease. Unfortunately, there are no large-scale clinical trials in this population, especially those receiving renal replacement therapy, so that strong evidence for treatment recommendations is scant. This review article provides the readers with the most recent insights on HCV infection both as cause and complication of chronic kidney disease, discusses pitfalls and limitations of current therapies, and reports on preliminary experience with novel therapeutic agents, as well as directions for future research.

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Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function

Cited by 75 publications

References 22 publications

Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection

Hepatitis C Infection and Chronic Renal Diseases

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