Pediatric Dosing of Ganciclovir and Valganciclovir: How Model‐Based Simulations Can Prevent Underexposure and Potential Treatment Failure

Jorga, Karin; Reigner, Bruno; Chavanne, Clarisse; Alvaro, Giuseppe; Frey, Nicolas

doi:10.1002/psp4.12363

Cited by 20 publications

(18 citation statements)

References 29 publications

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“…It is well recognized that the most obvious difference between children and adults is the body size ( Holford et al, 2013 ), which is generally parameterized by WT or BSA. 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) . In addition, considering that GCV is a renally excreted antiviral drug with high hydrophilicity, the renal function would significantly alter the clearance capacity of GCV ( Tsai et al, 2015 ).…”

Section: Discussioncontrasting

confidence: 80%

“…Currently, various dosing algorithms for intravenous ganciclovir have been proposed in published researches. And WT, BSA, eGFR or creatinine clearance values were used to compute individual GCV doses ( Jorga et al, 2019 ). According to the result of the covariate analysis, the WT-based algorithm was considered more appropriate than the BSA-based algorithm for dosage regimen design for critically ill pediatric patients.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

Shu

et al. 2021

Front. Pharmacol.

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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.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

Shu

et al. 2021

Front. Pharmacol.

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“…1 , whereas trough concentrations remained below the usual therapeutic threshold (e.g. < 0.5 µg/mL) [ 7 – 9 ] peak concentrations was high and AUC 0–12 h was close to 50 µg h/mL, which was within the therapeutic range (40–60 µg h/mL) suggested by some authors to treat CMV infection [ 10 , 11 ]. Eventually, viral load decreased quickly after 6 days at this dosage and became undetectable after 52 days.…”

Section: Case Presentationmentioning

confidence: 94%

The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Duval

Lemaître

Pertuisel³

et al. 2021

BMC Infect Dis

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Background Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. Case presentation We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0–12 h was measured at 51 μg h/mL, which was within the therapeutic range (40–60 μg h/mL). Afterward, viral load decreased and became undetectable. Conclusions This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

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“…It has a solubility of 3 mg/mL in water with pKa values of 2.2 and 9.4. Pediatric dosing in normal renal function ranges 20–40 mg/kg or 500–700 mg/m 2 every 8 h [ 113 , 114 ].…”

Section: The Next Wave Of Oral Liquid Formulation Development—formula...mentioning

confidence: 99%

Compounded Nonsterile Preparations and FDA-Approved Commercially Available Liquid Products for Children: A North American Update

Parrish

Ashworth²,

Löbenberg

et al. 2022

Pharmaceutics

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The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA)-approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms, and to propose lists of compounded nonsterile preparations (CNSPs) that should be developed as commercially available FDA-approved finished liquid dosage forms, as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and professionals are encouraged to continue to work together to improve the likelihood that patients will receive high-quality standardized extemporaneously compounded CNSPs and US-FDA-approved products.

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Pediatric Dosing of Ganciclovir and Valganciclovir: How Model‐Based Simulations Can Prevent Underexposure and Potential Treatment Failure

Cited by 20 publications

References 29 publications

Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Compounded Nonsterile Preparations and FDA-Approved Commercially Available Liquid Products for Children: A North American Update

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