title: Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.
abstract: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children.
  
  
  
  Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259.
  
  
  
  A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home.
  
  
  
  In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.
authors.affiliation: Department of Pharmacy, Riley Hospital for Children, Indianapolis, IN, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Pettit
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Columbia University Medical Center and New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Neu
authors.affiliation: Department of Pharmacy, St. Christopher's Hospital for Children, Philadelphia, PA, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Cies
authors.affiliation: Pediatric Pulmonology, Connecticut Children's Medical Center, Hartford, CT, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Lapin
authors.affiliation: Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Muhlebach
authors.affiliation: Department of Pharmacy, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Novak
authors.affiliation: Department of Pharmacy, Children's Medical Center, Dallas, TX, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Columbia University Medical Center and New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Saiman
authors.affiliation: Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT, USA joseph.kuti@hhchealth.org.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011446:Prospective Studies; D013845:Thienamycins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014481:United States
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem