title: Optimising piperacillin/tazobactam dosing in paediatrics.
abstract: Piperacillin/tazobactam, an intravenous antibacterial combination product, has recently been approved for paediatric (age 2 months to 17 years) use in the USA. The purpose of this analysis is to describe the basis for the dosing recommendations in this age group. Pharmacokinetic (PK) parameters and demographic covariates from 53 children enrolled in two paediatric studies were used in the analysis. Individual drug clearance (CL) values calculated by non-compartmental methods were available. The influence of demographic covariates on CL was investigated by non-linear regression. The analysis identified CL to be dependent on body weight. CL was also found to be influenced by age in paediatric patients<or=2 years, which is consistent with the expectation based on maturation of renal function. The population PK analysis and simulations, utilising comparable adult exposures as a basis to explore optimal dosing, resulted in the following dosing recommendations: for paediatric patients>or=9 months, a dose of 100/12.5 mg/kg every 8h showed exposures similar to adults; for paediatric patients aged 2-9 months, the dose of 100/12.5 mg/kg should be reduced by a factor of 0.8 (i.e. 80/10 mg/kg), likely due to immature renal function. Based upon this analysis, dosing recommendations for paediatric patients down to 2 months of age were incorporated in the labelling. No data were available to allow additional recommendations for paediatric patients<2 months of age to be made.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. christoffer.tornoe@fda.hhs.gov
authors.forename: Christoffer W
authors.initials: CW
authors.lastname: Tornøe
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Tworzyanski
authors.forename: Menfo A
authors.initials: MA
authors.lastname: Imoisili
authors.forename: John J
authors.initials: JJ
authors.lastname: Alexander
authors.forename: Joan M
authors.initials: JM
authors.lastname: Korth-Bradley
authors.forename: Jogarao V S
authors.initials: JV
authors.lastname: Gobburu
mesh_terms: D000367:Age Factors; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003710:Demography; D004348:Drug Labeling; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D012044:Regression Analysis; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin