Abstract
Objective: The present study aims to establish a population pharmacokinetic model of ganciclovir and optimize the dosing regimen in critically ill children suffering from cytomegalovirus related disease. Methods: A total of 104 children were included in the study. The population pharmacokinetic model was developed using the Phoenix NLME program. The final model was validated by diagnostic plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. To further evaluate and optimize the dosing regimens, Monte Carlo simulations were performed. Moreover, the possible association between systemic exposure and hematological toxicity were also monitored in the assessment of adverse events. Results: The ganciclovir pharmacokinetics could be adequately described by a one-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates. As showed in this study, the typical population parameter estimates of apparent volume of distribution and apparent clearance were 11.35 L and 5.23 L/h, respectively. Simulations indicated that the current regimen at a dosage of 10 mg/kg/d would result in subtherapeutic exposure, and elevated doses might be required to reach the target ganciclovir level. No significant association between neutropenia, the most frequent toxicity reported in our study (19.23%), and ganciclovir exposure was observed. Conclusion: A population pharmacokinetic model of intravenous ganciclovir for critically ill children with cytomegalovirus infection was successfully developed. Results showed that underdosing of ganciclovir was relatively common in critically ill pediatric patients, and model-based approaches should be applied in the optimizing of empiric dosing regimens.
Highlights
Ganciclovir (GCV) is a pro-drug nucleoside guanosine analogue that exhibits potent activity against herpesviruses, including cytomegalovirus (CMV) (Villarreal, 2001)
WT, body weight; BSA, body surface area; OFV, objective function value; AIC, Akaike information criterion; BIC, Bayesian information criterion; θCL, typical value of clearance; θVd, typical value of volume of distribution; SE, standard error; MF, factor for maturation; TM50, maturation half-time; c, Hill coefficient defining the steepness of the sigmoidal curve; k1, allometric exponent; k0, the exponent at a theoretical weight of 0 kg, BSA of 0 m2, or age at 0 years; kmax, a maximum decrease of the exponent; k50, the weight, BSA or age when a 50% drop in the maximum decrease of the exponent is achieved
Our study demonstrated that WT as a primary covariate was superior to BSA when allometric exponent model was used, which was inconsistent with the Jorga et al (2019)
Summary
Ganciclovir (GCV) is a pro-drug nucleoside guanosine analogue that exhibits potent activity against herpesviruses, including cytomegalovirus (CMV) (Villarreal, 2001). Following intravenous infusion, GCV was weakly bounded to plasma proteins (1–2%) over a concentration of 0.5–51 mg/L (McGavin and Goa, 2001), and it could penetrate the cerebrospinal fluid. Several studies showed that a large portion of the administered dose was eliminated from the body by glomerular filtration and renal tubular secretion as unchanged drug, which exhibited a good correlation between the clearance of GCV and creatinine clearance in adult patients (Roberts et al, 2014b; Al-Badr and Ajarim, 2018). As previous pharmacokinetic/pharmacodynamic studies confirmed, the desirable antiviral outcomes would require an area under drug plasma concentration-time curve over 24 h (AUC0-24) of 40–50 μg h/ml in both pediatric and adult patients following solid organ transplant (Wiltshire et al, 2005; Dong et al, 2018). It was estimated that nearly 80% patients may fail to achieve the target AUC level using the current pediatric GCV dosing regimen, increasing the risk of therapeutic failure in pediatric patients (Stockmann et al, 2015)
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