External Evaluation of Population Pharmacokinetic Models of Piperacillin in Preterm and Term Patients from Neonatal Intensive Care

Background and Objectives Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability...

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Published in:European journal of drug metabolism and pharmacokinetics 2024-09, Vol.49 (5), p.595-607
Main Authors: Boer-Pérez, Frida S., Lima-Rogel, Victoria, Mejía-Elizondo, Ana R., Medellín-Garibay, Susanna E., Rodríguez-Báez, Ana S., Rodríguez-Pinal, Cristian J., Milán-Segovia, Rosa del C., Romano-Moreno, Silvia
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Human Physiology
Medical Biochemistry
Original Research Article
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Pharmacy
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Summary:Background and Objectives Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance. This study aimed to evaluate the predictive performance of reported piperacillin population pharmacokinetic models for their application in a model-informed precision dosing strategy in preterm and term Mexican neonatal intensive care patients. Methods Published population pharmacokinetic models for piperacillin which included neonates in their study population were identified. From the reference models, structured models, population pharmacokinetic parameters, and interindividual and residual variability data were extracted to be replicated in pharmacokinetic software (NONMEM ® version 7.4). For the clinical study, a sampling schedule was designed, and 2–3 blood samples of 250 µL were taken from neonates who met the inclusion criteria. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. The clinical treatment data were collected, and piperacillin plasma concentrations were estimated using reference pharmacokinetic models for an a priori or Bayesian approach. Statistical methods were used in terms of bias and precision to evaluate the differences between observed and estimated neonatal piperacillin plasma concentrations with the different approaches and to identify the pharmacokinetic model that best fits the neonatal data. Results A total of 70 plasma samples were collected from 25 neonatal patients, of which 15 were preterm neonates. The overall median value (range) postnatal age, gestational age, body weight, and serum creatinine at the sampling collecting day were 12 (3–26) days, 34.2 (26–41.1) weeks, 1.78 (0.08–3.90) Kg, 0.47 (0.20–0.90) mg/dL, respectively. Three population pharmacokinetic models for piperacillin in infants up to 2 months were identified, and their predictive performance in neonatal data was evaluated. No pharmacokinetic model was suitable for our population using an a priori approach. The model published by Cohen-Wolkowiez et al. in 2014 with a Bayesian approach showed the best performance of the pharmacokinetic models evaluated in our neonatal data. The procedure r
ISSN:0378-7966
2107-0180
2107-0180
DOI:10.1007/s13318-024-00906-3