Population pharmacokinetics and dosing simulations of temocillin in liver transplanted paediatric patients: a prospective, open-label, non-randomized study

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 achievement of effective drug exposures in this patient group.

Methods: Patients aged 6-36 months received 25 mg/kg/12h (n=14) or 25 mg/kg/8h (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/12h, the unbound mean (±SD) C_max and C_min were 38±16 and 2±1 mg/L, respectively. For the 25 mg/kg/8h dose, the unbound C_max remained similar although the mean C_min 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 eGFR as significant covariates. Monte-Carlo simulations suggested that 90% Probability of Target Attainment (PTA) was achieved in both fluids with 25 mg/kg/12h for MICs ≤4 mg/L, eGFR ≤180 mL/min/1.73m² or weight ≥6 kg, and with 25 mg/kg/8h, for MICs ≤8 mg/L, GFR ≤120mL/min/1.73m² or weight ≥11 kg.

Conclusions: 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.