Limited predictability of amikacin clearance in extreme premature neonates at birth.
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.
Allegaert
Karel
K
Neonatal Intensive Care Unit, University Hospital Gasthuisberg, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
Anderson
Brian J
BJ
Cossey
Veerle
V
Holford
Nicholas H G
NH
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
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D000583:Amikacin; D001241:Aspirin; D007052:Ibuprofen