Population pharmacokinetics of ganciclovir following administration of valganciclovir in paediatric renal transplant patients.
OBJECTIVE
To develop a population pharmacokinetic model for valganciclovir in paediatric renal transplant recipients, identify covariates that explain variability, and determine valganciclovir dosage regimens for cytomegalovirus (CMV) prophylaxis in children.


METHODS
The pharmacokinetics of valganciclovir were described with plasma concentrations from 22 patients (age range 3-17 years) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using a bootstrap and visual predictive check. The dosage regimens of valganciclovir for CMV prophylaxis in children were simulated using the final model.


RESULTS
The mean population pharmacokinetic parameters were apparent systemic clearance (CL) 10.1L/h, apparent central volume of distribution 5.2 L, apparent peripheral volume of distribution 30.7 L, inter-tissue clearance 3.97 L/h, absorption rate constant 0.369 h-1 and lag-time 0.743 h. The covariate analysis identified creatinine clearance (CL(CR)) and bodyweight (WT) as individual factors influencing the apparent oral clearance: CL= 8.04 x (CL(CR)/89)(2.93) + 3.62 x (WT/28) L/h. The results of the simulation showed that for a typical patient (WT 28 kg and CL(CR) 89 mL/min), an area under the plasma concentration-time curve of 43 +/- 10.6 mg x h/mL will be achieved with valganciclovir 500 mg once daily.


CONCLUSIONS
The dosage regimens of valganciclovir for CMV prophylaxis have been defined using the final population pharmacokinetic model based on WT and CLCR for paediatric renal transplantation patients.
Zhao
Wei
W
Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
Baudouin
Véronique
V
Zhang
Daolun
D
Deschênes
Georges
G
Le Guellec
Chantal
C
Jacqz-Aigrain
Evelyne
E
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D044382:Population Groups; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D000077562:Valganciclovir
D000077562:Valganciclovir; D015774:Ganciclovir