Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens

Abstract

Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, to optimize dosing schemes. All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using nonlinear mixed-effect modeling. Monte Carlo simulations were used to optimize the dosing regimen to maintain the area under the concentration-time curve (AUC) in the preventive or therapeutic target. Among the 105 children (374 concentration-time observations) included, 78 received intravenous (i.v.) ganciclovir, 19 received oral valganciclovir, and 6 received both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe the bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and medical status of critically ill children were significantly associated with ganciclovir elimination. Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg of body weight/day oral or 15 to 20 mg/kg/day i.v. in children with normal eGFR and to 56 mg/kg/day oral or 20 to 25 mg/kg/day i.v. in children with augmented eGFR. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

Keywords: antiviral drug; children; population pharmacokinetics.

Copyright © 2021 American Society for Microbiology.

Figures

FIG 1

Observation data versus population predictions (upper left) and versus individual predictions (upper right) in the final model, noncensored data (full circle), and censored data (empty circle), represented with a log-log scale. The black line is the identity line. Normalized prediction distribution error versus time (bottom left) and predictions (bottom right). The horizontal line is the theoretical mean (0).

FIG 2

Prediction-corrected visual predictive check for i.v. (linear scale on the left and log-linear scale in the middle) and oral (right) administration. Colored areas represent 95% CIs of 5th, 50th, and 95th simulated percentiles. Lines are empirical (observed) 5th, 50th, and 95th percentiles. Dots are observed data. Full and empty circles are the noncensored and censored data, respectively.

FIG 3

Percentage of patients with an AUC0–24 below 40 mg/liter·h, between 40 and 80 mg/liter·h, between 80 and 120 mg/liter·h, and above 120 mg/liter·h after 2.5- to 25-mg/kg/day i.v. dose and 8- to 56-mg/kg/day oral dose according to eGFR.