Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance

Abstract

Critically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in β-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens. All children aged ≤ 18years, weighing more than 2.5kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC. We included 50 children with a median (range) postnatal age of 2.3years (0.1-18), body weight (BW) of 11.9kg (2.7-50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0-16), and estimated glomerular filtration rate (eGFR) of 142mL.min-1.1.73m-2 (29-675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3L.h-1 (0.71-10) and 0.33L.kg-1 (0.21-0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively. Unlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance. Registered at http://www.clinicaltrials.gov (NCT02539407).