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Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney
Laura Butragueño-Laiseca1, Nicolás Marco-Ariño2, Iñaki F Troconiz2
1Pediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain; Pediatrics Department, Universidad Complutense de Madrid, Spain; Maternal and Child Health and Development Research Network (REDSAMID), Institute of Health Carlos III, Madrid, Spain.
Insights
Standard piperacillin-tazobactam dosing is inadequate for critically ill children. Alternative continuous infusion regimens significantly improve drug exposure and target attainment in patients with and without continuous kidney replacement therapy.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Pharmacokinetics
Background:
- Piperacillin-tazobactam is frequently used in critically ill children.
- Current dosing regimens may not achieve optimal therapeutic targets in this population.
- The need for optimized dosing is particularly relevant for children undergoing continuous kidney replacement therapy (CKRT).
Purpose of the Study:
- To develop a population pharmacokinetic model for piperacillin in critically ill children.
- To evaluate the efficacy of standard piperacillin dosing in children with and without CKRT.
- To propose alternative dosing strategies to maximize target attainment.
Main Methods:
- A population pharmacokinetic model was developed using NONMEM 7.4.
- 429 piperacillin concentrations from 32 critically ill children (19 without CKRT, 13 with CKRT) were analyzed.
- Efficacy was assessed by estimating the percentage of patients achieving 90% free time above the minimum inhibitory concentration (fT>MIC) for various dosing regimens.
Main Results:
- A two-compartment model best described piperacillin pharmacokinetics.
- Renal, nonrenal, and hemofilter clearances were influenced by GFR, height, weight, and filter surface.
- Standard dosing achieved 90% fT>MIC in only 37% of children without CKRT and 54% with CKRT.
- A 24-hour continuous infusion of 200 mg/kg (CKRT) or 300 mg/kg (no CKRT) achieved 100% fT>MIC for MICs ≤16 mg/L.
Conclusions:
- Standard piperacillin dosing fails to ensure adequate systemic exposure in critically ill children, including those on CKRT.
- Prolonged and continuous infusion strategies demonstrate improved efficacy.
- Optimized dosing regimens are crucial for enhancing therapeutic outcomes in this vulnerable patient group.
Objectives:
Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment.
Methods:
Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population.
Results:
Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs.
Discussion:
In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.
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