Population Pharmacokinetics of Ganciclovir Following Oral Administration of its Prodrug Valganciclovir in Pediatric Renal Transplant Patients
Zhao W (1), Baudouin V (2), Zhang D (1) and Jacqz-Aigrain E (1)
1.Department of Pediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, Paris, France 2. Department of Nephrology, Hospital Robert Debré, Paris, France.
Introduction: Valganciclovir, the ester of ganciclovir and L-valine, is a prodrug of ganciclovir with improved oral absorption. It is well absorbed from the gastrointestinal tract and rapidly hydrolyzed in the intestinal wall and liver to ganciclovir that is eliminated via renal excretion. Population pharmacokinetic studies of valganciclovir in adults renal transplant patients have showed a large inter-individual variability in pharmacokinetic parameters. But there is no pharmacokinetic data in pediatric renal transplant patients. Therefore, valganciclovir is administered in pediatric patients without data validating the dosage associated with similar drug exposure to that observed in adults in the different pediatric age groups.
Objective: The aims of the study were to develop a pharmacokinetic model for valganciclovir in pediatric renal transplant recipients, to identify covariates that explain variability and to evaluate dosing regiment in children.
Patients and Methods: Twenty- two pediatric renal transplant recipients which consisted of 11 males and 11 females, with a mean (± standard deviation [SD]) age of 10±5 years (range, 3 to 17 years) and a mean (± SD) weight of 34±19 kg (range, 12 to 76 kg) were included in the study between 2003 and 2007. All the children at risk of CMV disease received the prophylactic therapy with valganciclovir for 3 months. In the case of positive CMV antigenemia, the patients received preemptive therapy with an initial course of IV ganciclovir infusion over 1h at a dose of 5mg/kg every 12 hours for 15 days, followed by valganciclovir at a dose of 15mg/kg twice daily for 3 months. The dose adjustment was based on through blood level (C0) of ganciclovir with the target > 0.5μg•h/mL.
The pharmacokinetics of valgancilovir were described with plasma level from twenty-two patients using nonlinear mixed - effects modeling (NONMEM) software. The first order (FO) method was used initially followed by the first order conditional estimation (FOCE) method to improve the estimation of pharmacokinetic parameters and their variability. The selection of covariates used a forward and backward selection processes. The final model was validated by the methods of Bootstrap and Visual Predictive Check. Using the final model, different dosing regiments were tested with NONMEM to find one suitable in pediatric patients. For each dosing scenario, 1000 replications were performed. AUC0-24 values were generated for each simulated patient. The entire procedure was performed in an automated fashion using Wings for NONMEM. The Visual Predictive Check were processed by R for NONMEM (v.20070911)
Results: A total of 164 ganaciclovir concentrations (28 Pk profiles) were available for population modeling and were best described with a 2-compartement model with a lag-time. Inter-individual and residual variability were best described by exponential model. Inter-individual variability was then estimated for CL, V2 and KA.
The popPK analysis identified creatinine clearance and bodyweight as individual factors influencing the apparent apparent clearance. , a nonlinear relationship between CL and CLCREA and a linear relationship between CL and bodyweight significantly improved the model, with the equation: CL =θ1× (CLCREA/median) θ2+θ3× (WT/median)
The final estimates of PK parameters ( CL apparent systemic clearance, V2 apparent central volume of distribution, V3 apparent peripheral volume of distribution, Q inter-tissue clearance, Ka absorption rate constant, lag-time), were CL= 8.04*(CLCREA/89)**2.93+3.62*(WT/28) L/h, V2= 5.2 L, V3=30.7 L, Q=3.97 L/h, Ka=0.369 h-1 , and lag-time=0.743 h.
Routine diagnostic individual residuals versus individual model-predicted values were symmetrically distributed and were mostly within about 1 unit of the null ordinate, indicating a good fit of the model to the data. Plots of individual weighted residuals versus time were distributed symmetrically in a band with no obvious trend and were mostly within approximately 3 unit of the null ordinate, indicating that no time-related factor affected the data and that no subject's data contributed to any marked deviation from the model.
The mean parameters estimates resulting from the bootstrap procedure very closely agreed with the respective values from the final population model different from the estimates previously obtained with the original dataset, indicating that the estimates for the population pharmacokinetic parameters in the final model were accurate and that the model was stable. (87% successful run, 1000 bootstrap)
The visual predictive check show that approximately 90% of the data of ganciclovir fit well within the 5th - 95th percentiles ( Exact Binomial Test, 9.2 % out of limits observed, the 95% confidence interval [5.24 , 14.7] ) and were symmetrically distributed around the median (Pearson's Chi-squared test, p = 0.1492)
Based on the results of simulation, for a typical patient (bodyweight 28 kg and creatinine clearance 89 mL/min), valganciclovir 500mg once daily can achieve a similar AUC 43 ± 10.6μg•h/mL. Then, we divided the patients into two groups. Group 1, the value of creatinine clearance is between 70 and 90 mL/min; Group2, between 90 and 120 mL/min. Each patient is stimulated 1000 times using the NONMEM. We found that in group 1, the dosing of 400 mg once daily can achieve the AUC 47 ± 14.4μg•h/mL and in group 2, the dosing of 700mg once daily can achieve the AUC43 ± 15.3μg•h/mL. We observed the dosing in second group is 1.8-fold higher than that in first group in order ensure the similar AUC. The correlation coefficient between dose-normalized AUC and creatinine clearance is 0.709.These results indicated that in the pediatric patients, the creatinine clearance is much more correlated with the clearance of valganciclovir, compared to the adult patients.
Conclusions: A population PK model for valgancilclovir in pediatric renal transplant patients has been developed. The simulations suggest that in patients with creatinine clearance 70-90 mL/min and 90-120 mL/min, respective dosing regiment were 400mg once daily and 700 mg once daily, which can achieve the similar referenced AUC in adults. (46.3 ± 15.2μg•h/mL, 900mg once daily).
 Wiltshire H. et al. Valganciclovir Solid Organ Transplant Study Group. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet; 2005; 44(5):495-507.