Background: Congenital cytomegalovirus (CMV) infection occurs when a fetus acquires the virus from a mother infected with CMV during pregnancy, transmitting it through the placenta. Currently, both ganciclovir (GCV) and its prodrug, valganciclovir (VGCV), are approved for the treatment and prophylaxis of CMV infections in immunocompromised patients and other CMV-associated diseases. However, no study has exclusively evaluated the population pharmacokinetics (PK) of both VGCV and GCV in symptomatic neonates and infants with congenital CMV infection.
Aims: The objectives of this study were: (i) To evaluate the variability in the pharmacokinetics of GCV in neonates and infants using a population PK approach. (ii) To identify the optimal predictor of allometric size and assess the influence of maturation and renal function on the PK of GCV.
Ethics: This study was conducted with the approval of the ethics committees of Nagasaki University Hospital (No. 19081922) and Nihon University (No. 19-014-1).
Methods: Neonates and infants diagnosed with congenital CMV infection and treated with VGCV oral formulation and/or GCV injections at Nagasaki University Hospital, Japan, were included in this study. The standard dosing regimen was 16 mg/kg of VGCV administered orally twice daily or 10 mg/kg of GCV administered intravenously over 1 hour once daily. Plasma GCV concentrations were measured using an LC/MS-8050 system (Shimadzu), with a lower limit of quantification of 0.04 mg/L. Population PK analysis was conducted using NONMEM 7.5.1. Model execution, bootstrapping, visual predictive checks, simulations, and results management were performed using Wings for NONMEM, while statistical and graphical analyses were conducted using R version 4.4.2. To evaluate GCV clearance maturation, sigmoidal or step functions were examined, using a linear independent combination of renal and non-renal clearance parameters. PK parameter values were standardized to a body weight of 70 kg with an allometric model.
Results: A total of 495 plasma GCV concentrations from 95 neonates and infants were analyzed to develop the population PK model. The final PK model was a one-compartment distribution model with first-order absorption and elimination for GCV. The population mean estimates of renal and non-renal clearance were 4.3 L/h and 2.1 L/h, respectively. The bioavailability of VGCV was approximately 50%, with an absorption lag time of 0.4 h. A sigmoidal function was selected to describe GCV clearance maturation, with a maturation half-life of 35 weeks and a sigmoidal slope parameter of 14.6.
Conclusion: A population PK analysis was conducted with a focus on the effects of body size and maturation on GCV clearance. The findings of this study enable the prediction of the PK of VGCV and GCV in the treatment of congenital CMV infection in neonates and infants.