title: Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus.
abstract: OBJECTIVE
  To determine patent ductus arteriosus (PDA) closure rates, and indomethacin (INDO) toxicity rates in neonates dosed with INDO using an individualized pharmacokinetic/pharmacodynamic (PK/PD) dosing approach. In addition, develop PD curves evaluating dose-response and concentration-response relationships for closure and renal toxicity, especially in select subgroups historically known as "poor responders" (<1000 g and > or = 10 days postnatal age).
  
  
  METHODS
  Prospective, cohort study.
  
  
  METHODS
  Level III neonatal intensive care unit.
  
  
  METHODS
  One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated.
  
  
  METHODS
  Patients initially received 0.25 mg/kg of INDO, followed immediately by 1 mg/kg of furosemide. INDO concentrations were obtained 2 hrs and 8 hrs after the dose and were assayed using high-performance liquid chromatography. Individualized PK parameters were calculated with subsequent INDO dosing based on the individualized PK variables to increase trough serum concentrations by 0.3-0.5 mg/L.
  
  
  RESULTS
  Ductal closure was successful in 127 patients (91%). Renal toxicity occurred in 21 (15%) patients and was temporary and reversible. No significant differences in response rates based on treatment weight or postnatal age were observed. PD curves were similar for neonates <1000 g vs. > or = 1000 g. PD curves were also similar for neonates with postnatal age <10 days vs. > or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age <10 days vs. > or = 10 days in total days of therapy (1.8 vs. 2.3 days), total number of doses required to close PDA (3.5 vs. 5.6 doses), critical INDO dose (0.9 vs. 1.4 mg/kg), critical INDO concentration (1.9 vs. 1.4 mg/L), and critical dose/critical concentration ratio (0.52 vs. 2.2).
  
  
  CONCLUSIONS
  These findings support the hypothesis that the poor PDA closure rates with INDO for neonates >10 days postnatal age are the result of pharmacokinetic differences only and that weight does not impact response rates. Individualized pharmacokinetic/pharmacodynamic dosing of INDO continues to achieve higher closure rate than current dosing standards. Patients historically known as poor responders significantly benefit from this dosing approach.
authors.affiliation: Greensboro Area Health Eduction Center and the Department of Neonatal Medicine, Women's Hospital of Greensboro, University of North Carolina at Chapel Hill, Greenboro, NC, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.forename: Peter
authors.initials: P
authors.lastname: Gal
authors.forename: J Laurence
authors.initials: JL
authors.lastname: Ransom
authors.forename: Rita Q
authors.initials: RQ
authors.lastname: Carlos
authors.forename: McCrae S
authors.initials: MS
authors.lastname: Smith
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davey
authors.forename: Mary Ann V T
authors.initials: MA
authors.lastname: Dimaguila
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Brown
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Schall
mesh_terms: D000367:Age Factors; D000465:Algorithms; D001724:Birth Weight; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D005865:Gestational Age; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007231:Infant, Newborn; D011446:Prospective Studies; D012016:Reference Values; D016896:Treatment Outcome
chemical_list: D002317:Cardiovascular Agents; D007213:Indomethacin