title: Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.
abstract: OBJECTIVE
  Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia.
  
  
  METHODS
  Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations.
  
  
  RESULTS
  Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range.
  
  
  CONCLUSIONS
  RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rower
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Jimmerson
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA.
authors.forename: Zayani
authors.initials: Z
authors.lastname: Sims
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA.
authors.forename: Tess
authors.initials: T
authors.lastname: Petersen
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: School of Public Health, University of Colorado, Aurora, CO, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Wolfe
authors.affiliation: Gilead Sciences Inc., Foster City, CA, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA.
authors.forename: Shyamasundaran
authors.initials: S
authors.lastname: Kottilil
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA jennifer.kiser@ucdenver.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D044967:Serum / Q000737:chemistry*; D000069474:Sofosbuvir / Q000008:administration & dosage*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D000069474:Sofosbuvir
keywords: SVR; anaemia; interferon-free therapy; red blood cells; ribavirin monophosphate