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Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants

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Abstract

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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Authors and Affiliations

  1. Department of Pharmacy, Children’s Hospital of Fudan University, Shanghai, China

    Zhiping Li, Yewei Chen, Qin Li, Di Cao, Dan Wu & Yiqing Zhu

  2. Department of Neonatology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China

    Wenjing Shi, Yun Cao & Chao Chen

  3. Department of Pediatric Neurology, Children’s Hospital of Fudan University, Shanghai, China

    Yi Wang

Authors
  1. Zhiping Li
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  2. Yewei Chen
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  3. Qin Li
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  4. Di Cao
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  5. Wenjing Shi
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  6. Yun Cao
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  7. Dan Wu
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  8. Yiqing Zhu
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  9. Yi Wang
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  10. Chao Chen
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Corresponding author

Correspondence to Chao Chen.

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Li, Z., Chen, Y., Li, Q. et al. Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants. Eur J Clin Pharmacol 69, 1223–1233 (2013). https://doi.org/10.1007/s00228-012-1413-4

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  • DOI: https://doi.org/10.1007/s00228-012-1413-4

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