Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment

Abstract

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

Fig 1

Ribavirin AUC_0–12 values for individual patients after multiple-dose administration. Open circles, individual patient values; solid lines, mean; dashed lines, median. A, group A (moderate renal impairment; CL_CR, 30 to 50 ml/min); B, group B (severe renal impairment; CL_CR, <30 ml/min); C, group C (end-stage renal disease with hemodialysis; CL_CR, <10 ml/min); D, group D (normal renal function; CL_CR, >80 ml/min). AUC, area under the concentration-time curve; RBV, ribavirin.

Fig 2

Predicted concentration-time profiles for patients with normal renal function. The green lines represent the predicted concentration-time profiles for patients in the study treated with the recommended dose of ribavirin. The black lines represent the median predicted concentration-time profile in the reference population receiving the recommended dose. The light and dark gray areas represent the 80% and 90% prediction intervals of the reference population, respectively. Patients treated with the 1,000-mg daily dose (400 mg in the morning and 600 mg in the evening) appear in the left panel, and patients treated with the 1,200-mg daily dose (600 mg twice daily) appear in the right panel. The dashed line represents the predicted profile for a single patient; this patient was enrolled in the normal renal function group (D) but had consistently low estimates of creatinine clearance (<80 ml/min) and was excluded from the analysis.

Fig 3

Predictive check for week 12 AUC_0–12. Histograms represent the distribution of simulated week 12 AUC_0–12 values for the study population. The dashed blue line is the mean of the simulated AUC_0–12, and the solid red line is the mean AUC_0–12 obtained by noncompartmental analysis.

Fig 4

RBV Css_avg in chronically HCV-infected patients with CKD. bid, twice daily; CKD, chronic kidney disease; Css_avg, average predicted concentration at steady state; ESRD, end-stage renal disease; HCV, hepatitis C virus; qd, once daily; RBV, ribavirin.