Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children

Thibault, Céline; Kassir, Nastya; Théôret, Yves; Varin, F.; Litalien, Catherine; Autmizguine, Julie

doi:10.22374/1710-6222.24.3.3

Cited by 2 publications

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“…Enrollment occurred from January 2016 to December 2017. Based on available PK parameters in the literature (25) and on a previous simulation study conducted by our group (20), enrollment was stratified by (i) age group (cohort 1, Ն2 months to 5 months of age; cohort 2, Ն6 months to 6 years of age) and (ii) clinical subpopulations (general pediatrics/surgery units, hematology-oncology units, and pediatric intensive care unit [PICU]). Children were excluded if they had insufficient venous access to allow extended infusion, a history of anaphylaxis to beta-lactams, stage 2 acute kidney injury or greater (defined as a doubling of the baseline serum creatinine [SCR] concentration, when available, or doubling of the normal value for age [42]), chronic renal insufficiency, or cystic fibrosis or if they were supported either by extracorporeal membrane oxygenation (ECMO) or by renal replacement therapy.…”

Section: Methodsmentioning

confidence: 99%

“…These elimination pathways undergo maturation during childhood, suggesting differences in TZP drug disposition in infants and young children relative to adults. In children, published results suggest benefits from using extended TZP infusions, but studies are mostly limited to simulation analyses in small specific populations (14)(15)(16)(17)(18)(19)(20), with only one PK study prospectively evaluating dosing regimens with extended infusions (21). In neonates, short TZP infusions were sufficient to achieve the PD target, suggesting no additional advantages of extended infusions in this population (22).…”

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confidence: 99%

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Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

Thibault

Lavigne²,

Litalien

et al. 2019

Antimicrob Agents Chemother

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Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

Thibault

Lavigne²,

Litalien

et al. 2019

Antimicrob Agents Chemother

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“…In situations where continuous infusion is not possible, the alternative option would be the Nichols dosing regimen of 400 mg/kg/d as an extended 3-h infusion (Nichols et al, 2015). For non-critically ill children, the current dosing advice could be continued, although a similar simulation study for non-critically ill children also suggested a slightly higher dose of 360 mg/kg/d and extended infusion in 2 h to reach adequate targets (Thibault et al, 2017). Additionally, as dose-related toxicity is limited, harmonizing the dose across the pediatric populations would be more practical.…”

Section: Piperacillinmentioning

confidence: 99%

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

et al. 2020

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Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept.Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation.Results: Three studies for piperacillin (critically ill children) and one for amikacin (critically ill pediatric burn patients) were included. Simulated concentration-time profiles were performed for a virtual dataset of 307 critically ill pediatric patients, age range 0.1–17.9 y. PTA for unbound piperacillin trough concentrations >16 mg/L was >90% only for continuous infusion regimens of 400 mg/kg/day vs. 9.7% for the current DPF dose (80 mg/kg/6 h, 30 min infusion). Amikacin PTA was >90% with 20 mg/kg/d, higher than the PTA of the DPF dose of 15 mg/kg/d (63.5%). Using our new decision framework, altered DPF doses were proposed for piperacillin (better PTA with loading dose plus continuous infusion), but not for amikacin (studied and target population were not comparable and risk for toxicity with higher dose).Conclusions: We show the feasibility to develop model-informed dosing guidelines for clinical implementation using existing pharmacokinetic data. This approach could complement literature and consensus-based dosing guidelines for off-label drugs in the absence of stronger evidence to support pediatricians in daily practice.

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Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children

Cited by 2 publications

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Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept

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