title: Target attainment analysis and optimal sampling designs for population pharmacokinetic study on piperacillin/tazobactam in neonates and young infants.
abstract: OBJECTIVE
  Population pharmacokinetic (popPK) analyses for piperacillin/tazobactam in neonates and infants of less than 2 months of age have been performed by our group previously. The results indicate that a dose of 44.44/5.56 mg/kg piperacillin/tazobactam every 8 or 12 h may not be enough for controlling infection in this population. In order to determine the appropriate dosing regimen and to provide a rationale for the development of dosing guidelines suitable for this population, further popPK studies of piperacillin/tazobactam would need to be conducted. The aim of the present study was to determine the appropriate dosing regimen and optimal sampling schedules in neonates and infants of less than 2 months of age.
  
  
  METHODS
  Pharmacodynamic profiling of piperacillin using Monte Carlo simulation was performed to explore the target attainment probability of different dosing regimens for infections caused by different isolated pathogens. D-optimal designs for piperacillin and tazobactam were conducted separately, and the times that overlapped were chosen as the final sampling scheme for future popPK studies in neonates and young infants of less than 2 months of age.
  
  
  RESULTS
  Our findings revealed that compared to the current empirical piperacillin/tazobactam dose regimen (50 mg/kg every 12 h by 5-min infusion in our hospital), the clinical outcome could be improved by increasing doses, increasing administration frequency, and prolonging intravenous infusion in neonates and infants of less than 2 months of age. The following optimal sampling windows were chosen as the final sampling scheme: 0.1-0.11, 0.26-0.29, 0.97-2.62, and 7.95-11.9 h administered every 12 h with 5-min infusion; 0.1-0.12, 0.39-0.56, 2.86-4.95, and 8.91-11.8 h administered every 12 h with 3-h infusion; 0.1-0.11, 0.22-0.29, 0.91-1.96, and 5.56-7.93 h administered every 8 h with 5-min infusion; 0.1-0.11, 0.38-0.48, 2.54-3.82, and 6.86-7.93 h administered every 8 h with 3-h infusion; 0.1-0.11, 0.25-0.28, 0.84-1.69, and 4.55-5.94 h administered every 6 h with 5-min infusion; and 0.1-0.11, 0.37-0.54, 3.13-3.72, and 5.57-5.99 h administered every 6 h with 3-h infusion.
  
  
  CONCLUSIONS
  The dosing regimen and sampling schedules proposed in this study should be evaluated in future popPK studies of piperacillin/tazobactam in neonates and infants. To the best of our knowledge, this is the first study that combined optimal sampling design with Monte Carlo simulation for designing popPK studies of piperacillin/tazobactam.
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China. zplifudan@126.com.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001800:Blood Specimen Collection; D003198:Computer Simulation; D004334:Drug Administration Schedule; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: Antibiotics; Monte Carlo simulation; Neonate; Optimal design; Piperacillin/tazobactam; Population pharmacodynamics