title: Population pharmacokinetic modeling of plasma and intracellular ribavirin concentrations in patients with chronic hepatitis C virus infection.
abstract: 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.).
authors: University of Southern California, Biomedical Engineering, Los Angeles, CA, USA.
authors: Liviawati S
authors: LS
authors: Wu
authors: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors: Joseph E
authors: JE
authors: Rower
authors: University of Colorado School of Medicine, Division of Gastroenterology and Hepatology, Aurora, Colorado, USA.
authors: James R
authors: JR
authors: Burton
authors: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors: Peter L
authors: PL
authors: Anderson
authors: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors: Kyle P
authors: KP
authors: Hammond
authors: Denver Health Medical Center, Denver, Colorado, USA.
authors: Fafa
authors: F
authors: Baouchi-Mokrane
authors: University of Colorado School of Medicine, Division of Gastroenterology and Hepatology, Aurora, Colorado, USA.
authors: Gregory T
authors: GT
authors: Everson
authors: Duke University, Durham, North Carolina, USA.
authors: Thomas J
authors: TJ
authors: Urban
authors: University of Southern California, Biomedical Engineering, Los Angeles, CA, USA.
authors: David Z
authors: DZ
authors: D'Argenio
authors: University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA Jennifer.Kiser@ucdenver.edu.
authors: Jennifer J
authors: JJ
authors: Kiser
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006207:Half-Life; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009842:Oligopeptides / Q000627:therapeutic use; D010766:Phosphorylation; D011153:Population; D012254:Ribavirin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012727:Sex Characteristics
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir
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