Individualized therapy and Bayesian estimator of ganciclovir exposure after oral administration of valganciclovir in pediatric renal transplant patients
Wei Zhao (1,2,3), Véronique Baudouin (3,4), May Fakhoury (1,3), Georges Deschênes (3,4) Evelyne Jacqz-Aigrain (1,2,3)
1. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France 2. Clinical Investigation Center CIC9202, INSERM, Paris, France 3. Université Paris VII, Paris, France 4. Department of Pediatric Nephrology, Assistance Publique - Hôpitaux de Paris, Paris, France
Background: A population pharmacokinetic study of valganciclovir, the prodrug of ganciclovir active against cytomegaloviruses, was previously conducted in pediatric renal transplant patients (referred below as the building group including 22 patients and 164 concentrations)[1]. Individualized therapy of valganciclovir was developed based on modeling strategy and validated in the present study.
Methods: The Bayesian estimator of valganciclovir exposure was obtained from the population pharmacokinetic parameters of the model building group. External validation was performed in an independent validation group, which consists of pharmacokinetic profiles from 15 patients (7 samples per patient).
Results: The target area under the curve (AUC0-24) of 40 to 50μg•h/mL is recommended in both adult and pediatric organ transplant patients. The current pediatric dosage regimen (Pediatric Dose (mg) = 7 x BSA x Creatinine clearance) does not always allow to reach the target but may be associated with either under or overdosing, even when taking into account identified covariates such as creatinine clearance and body surface area, The individual observed concentrations were well predicted by the model in the validation group. The Bayesian estimator of exposure using T0, T2 and T4 gave the best prediction of individual AUC. Mean prediction error was 0.1% [95%CI -4.1% to 4.0%] and mean prediction precision was less than 21.3%. Bland and Altman analysis showed that the average difference between measured and estimated AUCs was -0.27µg*h-1ml-1 (range -8.9 to 9.0µg*h-1ml-1).
Conclusion: AUC based dosage adaptation was necessary to optimize individual therapy in paediatric renal transplanted patients as variability is high. The Bayesian estimator of valganciclovir exposure, using three concentrations measured just before (T0) and 2 and 4 hours after drug intake was validated in the present study and can be used to accurately predict individual AUC. It will be useful to individualize valganciclovir therapy in pediatric renal transplant patients.
Reference:
[1]Zhao W, Baudouin V, Zhang D, Deschênes G, Le Guellec C, Jacqz-Aigrain E.Population pharmacokinetics of ganciclovir following administration of valganciclovir in paediatric renal transplant patients.Clin Pharmacokinet. 2009;48(5):321-8.