Population pharmacokinetics and dosing simulations of temocillin in liver-transplanted paediatric patients: a
Perrin Ngougni Pokem1, Xavier Stéphenne2, Xin Liu3
1Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Insights
Temocillin dosing in liver-transplant children needs adjustment for optimal effectiveness. Pharmacokinetic studies reveal current regimens may be inadequate for low-weight patients or those with high renal function, necessitating personalized dosing strategies.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Infectious Diseases
Background:
- Temocillin is a beta-lactam antibiotic used in pediatric liver transplant patients.
- Bacterial infections are a significant concern in this immunocompromised population.
- Optimizing antibiotic pharmacokinetics is crucial for effective treatment and infection prevention.
Purpose of the Study:
- To characterize the pharmacokinetics of temocillin in plasma and ascitic fluid of liver-transplanted children.
- To propose optimized temocillin dosing regimens for this specific patient group.
- To maximize the achievement of effective drug exposures and improve treatment outcomes.
Main Methods:
- A pharmacokinetic study involving pediatric patients aged 6-36 months receiving two different temocillin dosing regimens (25 mg/kg/12h or 25 mg/kg/8h).
- Measurement of total and unbound temocillin concentrations in plasma and ascitic fluid.
- Non-compartmental, population pharmacokinetic analyses, and Monte Carlo simulations were employed.
Main Results:
- Temocillin demonstrated saturable protein binding and good penetration into ascitic fluid (median 82%).
- Pharmacokinetic profiles were best described by a three-compartment model with body weight and estimated GFR as covariates.
- Monte Carlo simulations indicated that the 25 mg/kg/8h regimen achieved 90% probability of target attainment for higher MICs and GFR values compared to the 25 mg/kg/12h regimen.
Conclusions:
- Current temocillin dosing regimens may be insufficient for pediatric liver transplant patients with low body weight, high renal function, or infections caused by bacteria with high minimum inhibitory concentrations (MICs).
- Patient-specific factors are critical for optimizing temocillin dose selection.
- Further pediatric pharmacokinetic studies are essential for refining antibiotic dosing strategies in this vulnerable population.
Objectives:
Temocillin is a β-lactam antibiotic used for preventing or treating bacterial infections in liver-transplanted children. We characterized its pharmacokinetics in plasma and ascitic fluid and proposed dosing regimens that maximize the achievement of effective drug exposures in this patient group.
Methods:
Patients aged 6-36 months received 25 mg/kg/12 h (n = 14) or 25 mg/kg/8 h (n = 23). Total and unbound temocillin concentrations were measured in plasma and ascitic fluid. Drug safety was monitored. Non-compartmental and population pharmacokinetic analyses were performed, together with Monte Carlo simulations.
Results:
No safety concerns were reported. For 25 mg/kg/12 h, the unbound mean (±standard deviation) Cmax and Cmin were 38 ± 16 and 2 ± 1 mg/L, respectively. For the 25 mg/kg/8 h dose, the unbound Cmax remained similar although the mean Cmin increased to 5 ± 3 mg/L. Protein binding was saturable. Median penetration in ascitic fluid from plasma was 82% (min-max: 63-95%). A three-compartment model with first-order elimination best described unbound pharmacokinetic profiles in plasma and ascitic fluid, with body weight and estimated glomerular filtration rate (GFR) as significant covariates. Monte Carlo simulations suggested that 90% probability of target attainment was achieved in both fluids with 25 mg/kg/12 h for MICs ≤4 mg/L, estimated GFR ≤180 mL/min/1.73 m2 or weight ≥6 kg, and with 25 mg/kg/8 h, for MICs ≤8 mg/L, GFR ≤120 mL/min/1.73 m2 or weight ≥11 kg.
Discussion:
Although adequate in many instances, the current dosing regimen is likely inadequate for patients with low body weight, high renal function, or bacteria with high MIC, emphasizing the need for patient-specific factors to be considered in dose selection. These data support the importance of paediatric pharmacokinetic studies to optimize drug dosing regimens.
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