Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C

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 (M) 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 (DO), week 12 (W12), W12 + 1 day, and W24. Virological follow-up was performed at DO (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 DO AUC(0-12h) (3695 [1571-6916] versus 2937 [1266-4913] mu g/hour/L, P = 0.03) and DO AUC(0-4h) (2010 [615-3175] versus 1340 [622-2246] mu g/hour/L, P = 0.03). Patients with DO AUCs above the cut-off values defined by receiver operating characteristic curves (3014 mu g/hour/L and 1755 mu g/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). Conclusion: Ribavirin exposure at DO 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 mu g/hour/L at DO as a target for ribavirin dose adjustment.