Pharmacokinetics and safety of valaciclovir in children with Epstein-Barr virus illness.
OBJECTIVE
Valaciclovir has in vitro activity against Epstein-Barr virus (EBV) and, because of improved absorption with higher achievable serum concentrations, may be more effective than aciclovir in the treatment of EBV. No studies to date have evaluated the efficacy, safety or proper dosing of valaciclovir in children for the treatment of EBV infection. The objectives of this study were to determine the pharmacokinetics and safety of valaciclovir tablets and suspension in children with EBV illness.


METHODS
24 children with EBV illness were randomised to receive valaciclovir suspension 10 mg/kg or 20 mg/kg; eight children subsequently were crossed over and also received valaciclovir 500 mg tablets. Doses of either suspension or tablets were administered every 8 hours for four doses, and pharmacokinetic studies were performed to determine aciclovir serum concentrations. Samples for drug assay were obtained at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours. Samples were assayed by high performance liquid chromatography (HPLC) methods and aciclovir pharmacokinetics determined using non-compartmental analysis.


RESULTS
Valaciclovir pharmacokinetic parameters (mean +/- SD) in children who received tablets and suspension (normalised to 500 mg dose) were: maximum serum concentration (C(max)) 3.16 +/- 1.30 and 2.42 +/- 0.74 mg/L, time to maximum serum concentration (t(max)) 1.88 +/- 0.99 and 1.31 +/- 0.53 hours, half-life (t 1/2) 1.72 +/- 0.41 and 1.94 +/- 0.60 hours, apparent total systemic clearance (CL/F) 20.01 +/- 6.61 and 15.58 +/- 3.34 ml/min/kg, volume of distribution/bioavailability (Vd/F) 3.04 +/- 1.26 and 2.58 +/- 0.81 L/kg, and area under the concentration-time curve (AUC) 10.13 +/- 3.47 and 8.59 +/- 2.52 mg x h/L, respectively. There were no statistically significant differences in the pharmacokinetics of valaciclovir tablets versus suspension. The relative bioavailability of the valaciclovir tablets compared with the suspension was 115 +/- 32%. Valaciclovir was well tolerated, with gastrointestinal disturbances and headache being the most common adverse effects in a small number of subjects.


CONCLUSIONS
Valaciclovir is absorbed and achieves concentrations in children that appear to be effective for the treatment of herpes lesions. The pharmacokinetics of valaciclovir suspension and tablets are similar, and the pharmacokinetics of aciclovir after administration of valaciclovir to children are similar to historical observations of aciclovir pharmacokinetics in adults. Valaciclovir has a good safety profile and was well tolerated after oral administration in this group of children.
Simon
Michael W
MW
Department of Pediatrics, University of Kentucky, Lexington, Kentucky, USA mwsimon@mindspring.com
Fish
Douglas N
DN
Deeter
Robert G
RG
D000212:Acyclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000284:Administration, Oral; D000293:Adolescent; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy*; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D013535:Suspensions; D013607:Tablets; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000998:Antiviral Agents; D013535:Suspensions; D013607:Tablets; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir