Safety, Efficacy and Pharmacokinetics of Peginterferon α2a (40 kd) in Children With Chronic Hepatitis C

Abstract

Chronic hepatitis C virus (HCV) infection in children is a problem affecting thousands of children worldwide. Although standard interferon (INF) has better efficacy in pediatric patients than in adults, results in children with genotype 1 are poor; response rates to combination treatment with standard INF and ribavirin are better but the treatment requires thrice-weekly injections. The improved antiviral efficacy of weekly pegylated interferons relative to standard interferons in adults with chronic HCV infection suggests that pegylated interferons may also improve antiviral efficacy in children. We therefore investigated the pharmacokinetics, efficacy and safety of peginterferon alpha2a (pegINF-alpha2a) (40 kd) in 14 children ages 2 to 8 years with chronic hepatitis C (13 genotype 1, 1 non-1 genotype). Drug dose was calculated from each patient's body surface area (BSA) according to the formula BSA (m2)/(1.73 m2) x 180 microg, and patients were administered once-weekly subcutaneous injections for 48 weeks. Viral load and pharmacokinetic parameters were determined from blood drawn throughout the study and during follow-up. At week 24, the mean trough concentration was about 20% below values obtained from adults treated with pegINF-alpha2a, and the area under the curve from 0 to 168 hours was about 20% above adult values, suggesting that drug doses calculated from BSA achieved therapeutically adequate concentrations. Six of 14 patients (43%), all infected with genotype 1, achieved a sustained virological response. Adverse events were those commonly associated with INF-based treatment, and none was deemed serious. In conclusion, our findings provide a basis for larger studies evaluating the efficacy and safety of pegINF-alpha2a as monotherapy as well as in combination with ribavirin in pediatric patients with chronic hepatitis C.

Management of Chronic Hepatitis C: Consensus Guidelines

“…Standard IFN 3 MU/m 2 three times a week with ribavirin 15 mg/kg/day for 48 weeks yielded an SVR of 40% to 60% overall, and 70% to 100% in genotype 2 or 3 infection (79). PEG IFN-alpha-2a or -2b and ribavirin have been used in small numbers of HCV-infected children with SVR rates of 43% to 59% (higher in genotypes 2 and 3 than in genotypes 1 and 4) (80,81). Whether EVR can be used, as in adults, to stop therapy early in patients destined to be nonresponders is not clear.…”

PEGylated Proteins: Evaluation of Their Safety in the Absence of Definitive Metabolism Studies

“…This is in accordance with the prolonged exposure and higher AUC values obtained using PEG-Intron (PEG-Intron; EPAR). Treatments with PEGylated proteins such as PEG-interferon ␣ 2a (40 kDa; Pegasys) and PEGylated asparaginase do not reveal any specific adverse events linked to the PEG moiety (Avramis et al, 2002;Schwarz et al, 2003).Overall, the acute or chronic administration of PEG with a range of molecular weights by a range of routes has not led to any major toxicities, and signs of toxicity that do occur are only apparent at high dose. In light of this information, PEG can be considered to have a toxicological profile of very low concern in animals.…”

“…This is in accordance with the prolonged exposure and higher AUC values obtained using PEG-Intron (PEG-Intron; EPAR). Treatments with PEGylated proteins such as PEG-interferon ␣ 2a (40 kDa; Pegasys) and PEGylated asparaginase do not reveal any specific adverse events linked to the PEG moiety (Avramis et al, 2002;Schwarz et al, 2003).…”

Effects of pegylated interferon α-2a on hepatitis-C-virus-associated glomerulonephritis

“…Ribavirin is cleared by the kidneys and causes a dose-related hemolysis that can be severe and life threatening in patients with renal diseases [1]. Another study of pediatric patients with chronic HCV showed the safety and efficacy of PEG-IFN a-2a, both as monotherapy and in combination with ribavirin [10]. In order to decrease the risk of side effects, our patient was started on PEG-IFN a-2a monotherapy.…”