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

Pediatr Blood Cancer. 2015 Mar;62(3):477-82. doi: 10.1002/pbc.25287. Epub 2014 Oct 18.

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 ± 9.7 kg. 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 ± 0.076 L/h/kg, 0.199 ± 0.107 L/kg, 0.897 ± 1.050 h(-1) , and 1.427 ± 1.609 h(-1) , respectively. R(2) , bias, and precision for the Bayesian fit were 0.998, -0.032, and 2.2 µg/ml, respectively. At the MIC breakpoint of 16 µg/ml for Pseudomonas aeruginosa, PTAs for 50 mg/kg q4h as a 0.5 hr infusion was 93.9%; for 100 mg/kg q8h as 0.5 and 4 hr infusion: 64.6% and 100%; for 100 mg/kg q6h as 0.5 and 3 hr infusion: 86.5% and 100%; and for 400 mg/kg continuous infusion: 100%, respectively.

Conclusions: In children with fever and neutropenia, piperacillin/tazobactam dosing regimens that are administered every 4 hr or that employ prolonged or continuous infusions should be considered to optimize pharmacodynamic exposure.

Keywords: Pseudomonas aeruginosa; antibiotic dosing; febrile neutropenia; pediatric; pharmacokinetics.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / pharmacokinetics
  • Child
  • Child, Preschool
  • Female
  • Fever* / blood
  • Fever* / drug therapy
  • Humans
  • Male
  • Models, Biological*
  • Neoplasms* / blood
  • Neoplasms* / drug therapy
  • Neutropenia* / blood
  • Neutropenia* / drug therapy
  • Penicillanic Acid / administration & dosage
  • Penicillanic Acid / analogs & derivatives*
  • Piperacillin* / administration & dosage
  • Piperacillin* / pharmacokinetics
  • Piperacillin, Tazobactam Drug Combination
  • Pseudomonas Infections / blood
  • Pseudomonas Infections / drug therapy
  • Pseudomonas aeruginosa

Substances

  • Anti-Bacterial Agents
  • Piperacillin, Tazobactam Drug Combination
  • Penicillanic Acid
  • Piperacillin