Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants
Zhiping Li1, Yewei Chen, Qin Li
1Department of Pharmacy, Children's Hospital of Fudan University, Shanghai, China.
Insights
Population pharmacokinetic models for piperacillin/tazobactam in infants under 2 months indicate current dosing may be insufficient. Higher doses or more frequent administration may be needed for effective infection control in the neonatal intensive care unit (NICU).
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Pharmacology
- Infectious Disease Management
Background:
- Piperacillin/tazobactam is crucial for treating serious infections in neonates and infants.
- Limited pharmacokinetic data exists for this population, necessitating optimized dosing strategies.
- Neonatal intensive care unit (NICU) populations have unique physiological characteristics affecting drug disposition.
Purpose of the Study:
- To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants (<2 months).
- To determine appropriate dosing regimens for this vulnerable patient group.
- To provide a rational basis for preliminary dosing guidelines in the NICU.
Main Methods:
- A two-stage, open-label study involving 71 neonates and infants (<2 months) in the NICU.
- Analysis of 207 piperacillin and 204 tazobactam concentration-time data sets using nonlinear mixed-effect modeling (NONMEM VII).
- Model evaluation through bootstrap, visual predictive checks, and external validation in 20 additional patients.
Main Results:
- Median central clearance was 0.133 L/h/kg for piperacillin and 0.149 L/h/kg for tazobactam.
- Postmenstrual age (PMA) was a significant covariate, but bodyweight (BW) and postnatal age together were superior predictors of clearance.
- BW was the primary covariate for the volume of distribution; current dosing regimens achieved pharmacodynamic targets in approximately 67% of infants.
Conclusions:
- Population PK models accurately describe piperacillin/tazobactam disposition in infants <2 months.
- Current dosing strategies may be suboptimal for achieving therapeutic targets.
- Higher doses or more frequent administration of piperacillin/tazobactam may be required for effective infection control in this population.
Objectives:
To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population.
Methods:
A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients.
Results:
For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants.
Conclusions:
Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.
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