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Limited Sampling Strategies to Predict Ganciclovir Exposure after Valganciclovir Administration and to Reduce
A Facchin1,2, N Benyoub1, V Elie1
1Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France.
Insights
Valganciclovir dosing in pediatric renal transplant patients requires adjustment. A new limited sampling strategy (LSS) using just three blood samples accurately predicts drug levels, simplifying cytomegalovirus infection prevention.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Transplantation Medicine
- Pediatric Infectious Diseases
Background:
- Valganciclovir, a ganciclovir prodrug, is crucial for preventing cytomegalovirus (CMV) infection in pediatric renal transplant recipients.
- High pharmacokinetic variability necessitates therapeutic drug monitoring to achieve target area under the concentration-time curve (AUC0-24) of 40-60 μg·h/mL.
- Traditional AUC0-24 calculation using the trapezoidal method requires seven blood samples, posing a clinical challenge.
Purpose of the Study:
- To develop and validate a reliable, clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dosage in pediatric renal transplant patients.
- To reduce the number of blood samples required for therapeutic drug monitoring of valganciclovir.
Main Methods:
- Retrospective collection of pharmacokinetic data from pediatric renal transplant patients receiving valganciclovir for CMV prophylaxis.
- Calculation of ganciclovir AUC0-24 using the trapezoidal method as the reference.
- Development of LSS models using multilinear regression to predict AUC0-24 based on limited sampling times (e.g., T1h-T4h-T8h, T2h-T4h-T8h, T1h-T2h-T8h).
Main Results:
- Eighty patients (50 for development, 30 for validation) were included.
- Multilinear regression models using three samples (T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h) demonstrated the best predictive performance for AUC0-24.
- Average differences between reference and predicted AUC0-24 were minimal (-0.27, 0.34, and -0.40 μg·h/mL, respectively).
Conclusions:
- Valganciclovir dosage adaptation is essential in pediatric renal transplant patients to achieve therapeutic AUC0-24 targets.
- The developed LSS models using three blood samples offer a practical alternative to the traditional seven-sample method.
- These LSS models will aid in individualizing valganciclovir prophylaxis, improving patient outcomes and simplifying clinical management.
Abstract:
Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 60 μg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC0-24 with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUC0-24s were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC0-24 predictive performances with an average difference between reference and predicted AUC0-24 of -0.27, 0.34, and -0.40 μg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC0-24. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.
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