title: Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C.
abstract: The impact of ribavirin exposure on sustained virological response (SVR) in patients with chronic hepatitis C is unknown. Preliminary studies showed marked inter-individual variability of ribavirin concentrations despite dose adjustment for body weight (BW) and suggested there was a correlation between single time point concentrations and SVR. None of them evaluated the global exposure to ribavirin. This study was conducted to determine whether early ribavirin global exposure is related with SVR. An exploratory pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in genotype 1 hepatitis C patients treated with peginterferon alfa-2a and ribavirin (dose-adjusted for BW) for 12 weeks, to which amantadine was added for the following 36 weeks. Full and abbreviated ribavirin area under the concentration time curves (AUC(0-12h), AUC(0-4h)) were derived from plasma concentration profiles at day 0 (D0), week 12 (W12), W12 + 1 day, and W24. Virological follow-up was performed at D0 (0, 12, and 24 hours), W2, W4, W6, and monthly until W72 (TaqMan polymerase chain reaction, cut-off 15 international units/mL). Twenty-eight patients were enrolled in the study and 24 completed it. Patients with a SVR had a significantly higher D0 AUC(0-12h) (3695 [1571-6916] versus 2937 [1266-4913] microg/hour/L, P = 0.03) and D0 AUC(0-4h) (2010 [615-3175] versus 1340 [622-2246] microg/hour/L, P = 0.03). Patients with D0 AUCs above the cut-off values defined by receiver operating characteristic curves (3014 microg/hour/L and 1755 microg/hour/L for AUC(0-12h) and AUC(0-4h), respectively) had a significantly better chance of achieving an SVR than patients with AUCs under the thresholds (odds ratio = 16.0, 95% confidence interval 1.54-166.6, P = 0.02 and odds ratio = 8.9, 95% confidence interval, 1.4-56.6; P = 0.02).
  
  
  CONCLUSIONS
  Ribavirin exposure at D0 is significantly related to SVR. To our knowledge, this is the first study to give an early pharmacokinetic predictor of SVR. We propose a minimum AUC(0-4h) threshold of 1755 microg/hour/L at D0 as a target for ribavirin dose adjustment.
authors.affiliation: Centre Hospitalier Universitaire (CHU) Limoges, Internal Medicine Department, Limoges, France. veronique.loustaud-ratti@unilim.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Loustaud-Ratti
authors.forename: Sophie
authors.initials: S
authors.lastname: Alain
authors.forename: Annick
authors.initials: A
authors.lastname: Rousseau
authors.forename: Isabelle Fouchard
authors.initials: IF
authors.lastname: Hubert
authors.forename: François Ludovic
authors.initials: FL
authors.lastname: Sauvage
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
authors.forename: François
authors.initials: F
authors.lastname: Denis
authors.forename: Françoise
authors.initials: F
authors.lastname: Lunel
authors.forename: Paul
authors.initials: P
authors.lastname: Calès
authors.forename: Annie
authors.initials: A
authors.lastname: Lefebvre
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Fauchais
authors.forename: Eric
authors.initials: E
authors.lastname: Liozon
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vidal
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D015992:Body Mass Index; D004305:Dose-Response Relationship, Drug; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D011517:Prothrombin Time; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin