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  The Digestive Disease Week 2003 Conference
Orlando, Florida May 17-23, 2003
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Pegasys in Children in chronic hepatitis C: safety, efficacy and pharmacokinetics
  Reported by Jules Levin. This is part of ongoing coverage from the Digestive Disease Week Conference just completed.
Kathleen Schwarz (Johns Hopkins University School of Medicine) reported at the DDW Conference (May 17-22, 2003, Orlando, Fl) on a small pilot study of the safety, efficacy, and pharmacokinetics (blood levels) of Pegasys (peginterferon alfa-2a 40KD) in childfen with chronic hepatitis C.
Seroprevalence of HCV infection in children in the US is 0.2% aged less than 12 years and 0.4% in children aged 12 to 19 years. New infections are primarly acquired by perinatal transmission, by mother to newborn. Chronic HCV infection in children is typically asymptomatic with normal or near normal ALT levels. No therapies are currently approved by the FDA for treatment of chronic hepatitis C in children.
The role of antiviral therapy for chronic hepatitis C (CHC) in children remains unclear. Some studies have shown the safety and efficacy of standard interferon (IFN), with or without ribavirin (RBV), in children with CHC, but no data is available regarding the use of pegylated IFN in children.
The goal of this study is o investigate the safety, efficacy and pharmacokinetics (PK) of peginterferon alfa-2a (40KD) in children with CHC. This is a multicenter, open-label study of treatment-naive children with established chronic hepatitis C.
Children received Pegasys (peginterferon alfa-2a 40KD) once weekly for 48 weeks with a 24-week post-treatment follow-up. The dose was normalized for patient body surface area (BSA) ([180g/1.73 m2)] x patient BSA). Multiple blood samples were obtained to determine single-dose and multiple-dose PK. Predose blood sampling was measured at weeks 1, 4, 8,12, 24, 40 and 48 weeks. Post-dose blood sampling was performed at weeks 1 and 24 at 24, 96, and 168 hours after dose. Adverse events (AEs) were assessed by clinical exam. HCV RNA was tested using Roche Amplicor Monitor HCV Test v. 2.0.
There were 14 patients, 8 males, 6 females, aged 2-8 (median = 4.5) years were enrolled; majority (13/14) were Caucasian and genotype 1 (12/13). Chronic hepatitis C was acquired by vertical transmission in 11 patients. The mean weight was 44 lbs, the mean height 106.9 cm. Mean ALT was 73.5and mean AST was 66.9. 10 children had viral load less than 850,000 copies/ml and 4 had greater than 850,000 copies/ml. All 14 children did not have cirrhosis.
In dosing, height, age, gender, body weight, and body surface area were assessed. After administration of the first peginterferon alfa-2a (40KD) dose, there was rapid and sustained absorption with mean concentrations of 22.3 ng/ml and 19.0 ng/ml at 24 and 96 hours postdose. The mean individual pediatric trough concentrations at week 24 ranged from 5 to 35 ng/ml, and the mean trough was 20 ng/ml which was insignificantly different from adult trough data which is 25 ng/ml for adults. AUC 0-168hrs varied from about 1000 to 9000 ng/ml for the children with a mean of 5700 ng/ml over the 168 hour dose interval and these were done at week 24, and was insiginificantly greater at 5700 ng.h/ml than for adults at 4548 ng.h/ml. Peginterferon alfa-2a (40KD) concentrations increased 1.5- 2.5-fold before reaching steady state by week 12.
At weeks 24, 48, and 72, 57% (8/14), 50% (7/14) and 42% (6/14) of patients, respectively, were HCV RNA negative. Most frequently reported AEs were pyrexia, headache, vomiting, injection site reactions, irritability, anorexia and abdominal pain; no serious AEs were observed. The majority of these AEs were mild in intensity. 5 patients had dose adjustments due to low absolute neutrophil counts; the lowest absolute neutrophil count for each patient was:
0.40 x 109/L
0.60 x 109/L
0.70 x 109/L
0.60 x 109/L
0.50 x 109/L
Characteristics of the 6 sustained responders: 5 male, 6 genotype 1, 5 viral load below 850,000 copies/ml, and 6 had ALT less than 3 times the upper limit of normal.
5 patients withdrew prematurely after completing 24 to 47 weeks of treatment. Reasons for withdrawal included: adverse events/intercurrent illness (2 for elevated ALT, 1 for elevated triglycerides); administrative error (last dose not taken; refusal to continue treatment.
The authors concluded that Pegasys dosing with a correction for body surface area is appropriate in children. A once weekly dose of 180 ug/1.73 m2 x BSA (104 ug/m2) provides a predicted Ctrough of about 20 ng/ml and AUC of about 5700 ng.h/ml after 24 weeks. Exposure values are generally similar to those in adults treated with the approved dose of Pegasys 180 ug/week. Pegasys produced sustained virologic responses in 42% of children aged 2 to 8 years, similar to that in adults. These results support further study of peginterferon alfa-2a (40KD), with and without RBV, in children with CHC.