Piperacillin Population Pharmacokinetics in Plasma and Peritoneal Fluid and Dosing Optimization in Children...

Piperacillin-tazobactam is frequently used in children undergoing liver transplantation (LT), yet its pharmacokinetics (PK) in this population remains poorly characterized. We aimed to develop a population pharmacokinetic model for piperacillin in plasma and peritoneal fluid in children undergoing LT and to optimize dosing regimen for this population. We conducted a retrospective, single-center, observational study including all children receiving piperacillin-tazobactam as prophylaxis for LT and had at least one piperacillin concentration in both plasma and peritoneal fluid. PK analysis was conducted using nonlinear mixed effect modeling (Monolix) and was part of Optimome study. We included 31 patients with a median (range) age of 4 years (4 months-17 years). A total of 172 plasma and 146 peritoneal fluid samples were analyzed. Plasma concentrations were best fitted by a one-compartment model with first-order elimination. A virtual effect site compartment was added to adequately describe piperacillin concentrations in plasma and peritoneal fluid. Allometrically scaled body weight (pre-transplant and current values) and glomerular filtration rate (eGFR) were identified as significant covariates. Median (range) peritoneal/plasma AUC_0-24h ratio was 72 (45-94) %. Simulations showed that optimal dosing regimens ranged from 300 mg/kg/day (q6h over 3 hours) to 400 mg/kg/day as a continuous infusion, depending on the PK target (i.e., fT_{>1 × MIC} or fT_{>4 × MIC}) and patient eGFR. In children undergoing LT, body weight and renal function explained some of the between subject variability for piperacillin PK. Higher dosing regimen combined with therapeutic drug monitoring is necessary to optimize exposure in plasma and at surgical site.