title: 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.
  
  
  METHODS
  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.
authors.affiliation: St. Christopher's Hospital for Children, Philadelphia, Pennsylvania; Drexel University College of Medicine, Philadelphia, Pennsylvania; Alfred I duPont Hospital for Children, Wilmington, Delaware.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Cies
authors.forename: Jaimi
authors.initials: J
authors.lastname: Jain
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005334:Fever / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009503:Neutropenia / Q000097:blood / Q000188:drug therapy; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy; D011550:Pseudomonas aeruginosa
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: Pseudomonas aeruginosa; antibiotic dosing; febrile neutropenia; pediatric; pharmacokinetics