Leveraging Clinical Data to Enhance the Performance Evaluation of Ceftriaxone Population Pharmacokinetic Models in
Stef Schouwenburg1,2, Tim Preijers3,4, Alan Abdulla3,4
1Department of Hospital Pharmacy, Erasmus University Medical Centre, Postal Box 2040, 3000 CA, Rotterdam, The Netherlands. s.schouwenburg@erasmusmc.nl.
Insights
External validation of ceftriaxone population pharmacokinetic (popPK) models in pediatric intensive care units (PICUs) revealed inadequate performance. Current dosing may require re-evaluation to prevent toxicity and optimize treatment for critically ill children.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Antibiotic Dosing
Background:
- Sepsis is common in pediatric intensive care units (PICUs).
- Ceftriaxone is a frequently used antibiotic for pediatric infections.
- Limited data exist on ceftriaxone population pharmacokinetics (popPK) in children.
Purpose of the Study:
- To externally validate existing ceftriaxone popPK models for pediatric ICU patients.
- To assess the suitability of these models for individualized dosing.
- To identify the best-performing model for this population.
Main Methods:
- Utilized data from the prospective EXPAT Kids PK/PD study.
- Implemented and evaluated models using NONMEM software.
- Assessed model accuracy with goodness-of-fit and visual predictive checks.
- Evaluated predictive performance using error metrics (RPE, RMSE, MAPE).
Main Results:
- Significant variability in predictive performance among evaluated models.
- Models generally overpredicted ceftriaxone concentrations.
- Unbound ceftriaxone popPK models showed inadequate performance.
- No models met all predefined accuracy and precision thresholds.
Conclusions:
- The external dataset showed high ceftriaxone trough concentrations, suggesting potential overdosing.
- Current ceftriaxone dosing regimens may need re-evaluation to minimize toxicity.
- Future research should focus on optimizing ceftriaxone dosing, especially for meningitis, balancing exposure and trough concentrations.
- External evaluation of popPK models is crucial for the PICU population.
Introduction:
Sepsis affects approximately 8% of pediatric intensive care unit (PICU) admissions in high-income countries. Ceftriaxone, a broad-spectrum beta-lactam antibiotic, is widely used for treating severe infections and bacterial meningitis in children. Despite its frequent use, limited studies address the population pharmacokinetic (popPK) of ceftriaxone in pediatrics. External validation of popPK models is essential to confirm their suitability for individualized dosing in PICU patients, enabling selection of the model best suited to this population.
Methods:
This study used data from the EXPAT Kids study, a prospective pharmacokinetics /pharmacodynamics (PK/PD) study. The included popPK models were implemented in NONMEM, with diagnostic goodness-of-fit and visual predictive check analyses performed to assess model accuracy. Predictive performance was evaluated using the relative prediction error, relative root mean square error, and mean (absolute) percentage error.
Results:
The predictive performance of the evaluated models varied widely. The included models showed only modest performance and generally seemed to overpredict ceftriaxone concentrations. Unbound ceftriaxone popPK models did not perform adequately. None of the models met all the predefined thresholds for accuracy and precision.
Conclusions:
Our external dataset comprised high ceftriaxone trough concentrations, indicating re-evaluation of current ceftriaxone dosing regimens to minimize the risk of overdosing and prevent toxicity. Future research should focus on the fine dosing balance for ceftriaxone, especially in patients with meningitis, by considering adequate exposure while preventing high trough concentrations. Model-informed precision dosing may enhance the use of the optimal individual dosage for critically ill children. However, our findings highlight the importance of externally evaluating ceftriaxone popPK models in the PICU population.
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