title: Evaluating renal function and age as predictors of amikacin clearance in neonates: model-based analysis and optimal dosing strategies.
abstract: We aimed to compare the performance of renal function and age as predictors of inter-individual variability (IIV) in clearance of amikacin in neonates through parallel development of population pharmacokinetic (PK) models and their associated impact on optimal dosing regimens.
  
  
  
  Amikacin concentrations were retrospectively collected for 149 neonates receiving amikacin (post-natal age (PNA) between 4-89 days). Two population PK models were developed in parallel, considering at least as predictors current body weight (WT), in combination with either creatinine clearance (CLcr ) or age descriptors. Using stochastic simulations for both renal function or age-based dosing, we identified optimal dosing strategies that were based on attainment of optimal peak- (PCC) and trough target concentration coverage (TCC) windows associated with efficacy and toxicity.
  
  
  
  The CLcr and age-based population PK models both included current body weight (WT) on CL, central distribution volume and intercompartmental clearance, in combination with either CLcr or PNA as predictors for IIV of clearance (CL). The WT-CLcr model explained 6.9% more IIV in CL compared with the WT-PNA model. Both models successfully described an external dataset (n = 53) of amikacin PK. The simulation analysis of optimal dose regimens suggested similar performance of either CLcr or PNA based dosing.
  
  
  
  CLcr predicted more IIV in CL, but did not translate into clinically relevant improvements of target concentrations. Our optimized dose regimens can be considered for further evaluation to optimize initial treatment with amikacin.
authors.affiliation: Biochemistry Service, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.|Biochemistry Service, Hôpital Européen Georges Pompidou, Paris, France.|Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universitat de Barcelona, Spain.
authors.forename: Sílvia M
authors.initials: SM
authors.lastname: Illamola
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universitat de Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Colom
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: J G Coen
authors.initials: JG
authors.lastname: van Hasselt
mesh_terms: D000375:Aging / Q000378:metabolism*; D000583:Amikacin / Q000097:blood / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D012189:Retrospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin; D003404:Creatinine
keywords: amikacin; dosing guidelines; modelling and simulation; paediatric clinical pharmacology; population pharmacokinetics