Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

Area of Science:

• Pharmacology
• Pediatrics
• Infectious Diseases

Background:

• Cytomegalovirus (CMV) infections pose a significant threat to critically ill children.
• Ganciclovir is a primary antiviral agent used for CMV treatment.
• Optimizing ganciclovir dosing in pediatric populations, especially the critically ill, remains a challenge.

Purpose of the Study:

• To develop a population pharmacokinetic (PopPK) model for ganciclovir in critically ill children.
• To optimize ganciclovir dosing regimens to achieve therapeutic concentrations.
• To investigate the relationship between ganciclovir exposure and hematological toxicity.

Main Methods:

• A population pharmacokinetic model was developed using Phoenix NLME software.
• Model validation included diagnostic plots, nonparametric bootstrap, and visual predictive checks.
• Monte Carlo simulations were employed to evaluate and optimize dosing strategies.
• Adverse events, particularly neutropenia, were monitored for association with ganciclovir exposure.

Main Results:

• A one-compartment model with first-order elimination, incorporating body weight and estimated glomerular filtration rate, adequately described ganciclovir pharmacokinetics.
• Typical population estimates for apparent volume of distribution and clearance were 11.35 L and 5.23 L/h, respectively.
• Simulations indicated that the current 10 mg/kg/d regimen leads to subtherapeutic exposure, suggesting a need for dose escalation.
• Neutropenia, observed in 19.23% of patients, showed no significant association with ganciclovir exposure.

Conclusions:

• A robust population pharmacokinetic model for intravenous ganciclovir in critically ill children with CMV infection was established.
• Underdosing of ganciclovir is prevalent in this vulnerable pediatric group.
• Model-based approaches are essential for optimizing empiric ganciclovir dosing regimens in critically ill children.