Exposure Levels of Ribavirin Similar in Paediatric and Adult Patients With Hepatitis C: Presented at ACCP

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Title: Exposure Levels of Ribavirin Similar in Paediatric and Adult Patients With Hepatitis C: Presented at ACCP
URL: http://www.pslgroup.com/dg/22CDDA.htm
Doctor's Guide
September 19, 2008

By Crina Frincu-Mallos, PhD

PHILADELPHIA -- September 19, 2008 -- Exposure levels of ribavirin are similar in paediatric patients as in adults with hepatitis C virus (HCV) infection, when the ribavirin dose is normalised to body weight, researchers reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting.

Christine Xu, PharmD, Schering-Plough Research Institute, Kenilworth, New Jersey, presented the data here on September 14.

Ribavirin, a nucleoside analogue, is an essential component of antiviral therapy for chronic hepatitis C. When used in an adult population in combination with pegylated interferon (PEG-IFN) alfa-2b, 54% of patients had a sustained virological response.(1)

The global, multicentre, open-label, phase 1b/3 study was conducted to develop an appropriate population model of ribavirin in paediatric patients with HCV infection, with a secondary objection of evaluating the effect of covariates on ribavirin pharmacokinetics, said Dr. Xu and colleagues in his poster presentation.

Dr. Xu and colleagues enrolled 51 boys and 56 girls with HCV infection aged between 3 and 17 years old and with a weight of <=90 kg. These patients were divided according to age: 3 to 5 years old (n = 22); 6 to 11 years old (n = 45); and 12 to 17 years old (n = 40).

Patients had a mean weight of 39 kg (range, 13.5-87 kg), mean body mass index was 18.8 kg/m² (range, 12.8-33.1 kg/m²), mean body surface area was 1.21 m² (range, 0.6-2.08 m²), and mean creatinine clearance was 91.8 mL/min (range, 35.2-184 mL/min).

All patients were treated with subcutaneous PEG-IFN alfa-2b at a dose of 60 mcg/m²/week in addition to oral ribavirin 15 mg/kg/day. Based on their HCV genotype and viral load at baseline, patients were assigned either to a 48-week treatment regimen (n = 86; HCV genotype 1, 4, 5, 6, and HCV genotype 3 with viral load >=600,000 IU/mL) or a 24-week regimen (n = 21; HCV genotype 2 and HCV genotype 3 with viral load <600,000 IU/mL). Patients were followed for 24 weeks.

From these patients, the investigators were able to obtain 726 ribavirin plasma concentrations; all included in the population PK analysis. To analyse these concentrations, Dr. Xu and colleagues used a non-linear mixed-effects modelling approach with a first order conditional estimation method.

The PK of ribavirin are best described by a 2-compartment model with first order absorption and first order elimination, explained Dr. Xu. The covariate analysis included serum creatinine, creatinine clearance, ALT, and HCV genotype.

Interindividual variance was 24.5% for apparent clearance (CL/F) of ribavirin and 72.2% for the apparent volume of distribution (Vz/F). Body weight was the significant covariate for CL/F and Vz/F.

Body weight-normalised CL/F of ribavirin was similar across the paediatric age groups (mean values ranging from 0.25 to 0.3 L/hr/kg). It was also similar to the CL/F for adults (0.27 L/hr/kg), noted Dr. Xu.

Based on these results, the investigators concluded that exposure levels of ribavirin were similar in paediatric patients and adults with HCV when the ribavirin dose was normalised to body weight (15 mg/kg/day).

Funding was provided by Schering-Plough Research Institute.

1. Manns MP et al. Lancet. 2001;358:958-965.

[Presentation title: Population Pharmacokinetic Investigation of Ribavirin in Pediatric Subjects Infected With Hepatitis C Virus. Abstract 122]

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