Population pharmacokinetics of the piperacillin component of piperacillin/tazobactam in pediatric oncology patients with fever and neutropenia

Abstract

Background: To describe the population pharmacokinetics of the piperacillin component of piperacillin/tazobactam. Procedure: This pharmacokinetic study included 21 pediatric (age 3-10 years) patients receiving piperacillin/tazobactam to treat fever with neutropenia. Each patient contributed 1-3 blood samples for piperacillin concentration determination. Population pharmacokinetic analyses were conducted using Pmetrics software. A 5,000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for multiple dosing regimens, using 50% of free drug time above the minimum inhibitory concentration (MIC) as the primary pharmacodynamic threshold. Results: Mean±SD body weight was 28.5±9.7kg. Piperacillin concentration data best fit a two-compartment model with linear clearance, using total body weight as a covariate for clearance (CLθ) and volume of the central compartment (Vcθ). Population estimates for CLθ, Vcθ, and intercompartment transfer constants were 0.204±0.076L/h/kg, 0.199±0.107L/kg, 0.897±1.050h-1, and 1.427±1.609h-1, respectively. R2, bias, and precision for the Bayesian fit were 0.998, -0.032, and 2.2μg/ml, respectively. At the MIC breakpoint of 16μg/ml for Pseudomonas aeruginosa, PTAs for 50mg/kg q4h as a 0.5hr infusion was 93.9%; for 100mg/kg q8h as 0.5 and 4hr infusion: 64.6% and 100%; for 100mg/kg q6h as 0.5 and 3hr infusion: 86.5% and 100%; and for 400mg/kg continuous infusion: 100%, respectively. Conclusions: In children with fever and neutropenia, piperacillin/tazobactam dosing regimens that are administered every 4hr or that employ prolonged or continuous infusions should be considered to optimize pharmacodynamic exposure.