title: Limited predictability of amikacin clearance in extreme premature neonates at birth.
abstract: OBJECTIVE
  Identify and quantify factors describing variability of amikacin clearance in preterm neonates at birth.
  
  
  METHODS
  Population pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24-30 weeks; weight 1.07, SD 0.34, range 0.45-1.98 kg, postnatal age < 72 h]. Covariate analysis included weight, PCA, Apgar score, prophylactic administration of a nonsteroidal anti-inflammatory drug (NSAID) to the neonate, maternal indomethacin and betamethasone administration, and chorioamnionitis.
  
  
  RESULTS
  A one-compartment linear disposition model with zero order input (0.3 h i.v. infusion) and first-order elimination was used. The population parameter estimate for volume of distribution (V) was 40.2 l per 70 kg. Clearance (CL) increased from 0.486 l h(-1) per 70 kg at 24 weeks PCA to 0.940 l h(-1) per 70 kg by 30 weeks PCA. The population parameter variability (PPV) for CL and V was 0.336 and 0.451. The use of a NSAID (either aspirin or ibuprofen) in the first day of life reduced amikacin clearance by 22%. Overall 65% of the variability of CL was predictable. Weight explained 48%, PCA 15% and NSAIDs 2%.
  
  
  CONCLUSIONS
  Size and post-conception age are the major contributors to clearance variability in extreme premature neonates (<31 weeks PCA). The large (35% of total) unexplained variability in clearance reinforces the need for target concentration intervention to reduce variability in exposure to a safe and effective range.
authors.affiliation: Neonatal Intensive Care Unit, University Hospital Gasthuisberg, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: Veerle
authors.initials: V
authors.lastname: Cossey
authors.forename: Nicholas H G
authors.initials: NH
authors.lastname: Holford
mesh_terms: D000367:Age Factors; D000583:Amikacin / Q000097:blood / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D001424:Bacterial Infections / Q000517:prevention & control*; D001724:Birth Weight; D049628:Body Size / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D000583:Amikacin; D001241:Aspirin; D007052:Ibuprofen