Pharmacokinetic/Pharmacodynamic Modelling and Monte Carlo Simulations to Predict Cytomegalovirus Viral Load in Pediatric Transplant Recipients Treated with (val)Ganciclovir

Background and Objectives Cytomegalovirus (CMV) infection poses significant challenges in pediatric transplant recipients. Ganciclovir and its prodrug valganciclovir are primary treatments because of their potent antiviral effects. Balancing efficacy and toxicity is particularly critical in children. This study aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for (val)ganciclovir and assess the relationship between area under the concentration-time curve (AUC) and CMV viral loads via Monte Carlo simulations. Methods We conducted a retrospective analysis including 184 viral load samples from 36 transplanted children treated with ganciclovir/valganciclovir. We developed a population pharmacodynamic model using Monolix and performed Monte Carlo simulations to assess viral load decline with varying AUCs. Internal validation was performed using goodness-of-fit plots and bootstraps. Results We used a viral turnover model with stimulated degradation to model the pharmacodynamic data. Model validation showed no bias or misspecification. Simulations indicated that maintaining an AUC(0-24) >= 40 mg<middle dot>h/L achieved an 85.4% probability of undetectable viral load after 28 days of therapy. An AUC(0-24) > 30 mg<middle dot>h/L provided 80.9% probability of reducing viral loads by - 1 log after 2 weeks. AUC(0-24) values > 60 mg<middle dot>h/L offered minimal incremental benefits. Conclusion The pharmacodynamic model accurately predicted observed data. Simulations indicated that maintaining a ganciclovir plasma AUC(0-24) around 40-60 mg<middle dot>h/L maximized antiviral efficacy. An AUC(0-24) > 60 mg<middle dot>h/L might increase the risk of adverse events without providing additional efficacy.