title: Using pharmacokinetic modelling to improve prescribing practices of intravenous aminophylline in childhood asthma exacerbations.
abstract: To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline.
  
  
  
  Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software.
  
  
  
  Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those <10 mg/L, and adverse effects occurred in 57%. Therapeutic drug monitoring (TDM) data correlated well with PBPK model. PBPK modelling of a 5 mg/kg iv loading dose (≤18yr) shows a mean Cmaxof 8.99 mg/L (5th-95th centiles 5.5-13.7 mg/L), with 70.3% of subjects <10 mg/L, 29.4% achieving 10-20 mg/L, and 0.1% > 20 mg/L. For an aminophylline infusion (0-12 y) of 1.0  mg/kg/h, the mean steady state infusion concentration was 16.4 mg/L, (5th-95th centiles 5.3-32 mg/L), with 26.8% having a serum concentration >20 mg/L. For 12-18yr receiving 0.5  mg/kg/h infusion, the mean steady state infusion concentration was 9.37 mg/L (5th-95th centiles 3.4-18 mg/L), with 59.8% having a serum concentration <10 mg/L.
  
  
  
  PBPK software modelling correlates well with clinical data. Current aminophylline iv loading dosage recommendations achieve levels <10 mg/l in 70% of children. Routine TDM may need altering as low risk of toxicity (>20 mg/l).
authors.affiliation: Medical School, University of Liverpool, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Cooney
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK.
authors.forename: Antonia
authors.initials: A
authors.lastname: McBride
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lilley
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Sinha
authors.affiliation: Simcyp, Sheffield, UK.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Johnson
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK; Department of Women's and Children's Health, University of Liverpool, UK; NIHR Alder Hey Clinical Research Facility, Alder Hey Children's Hospital, Liverpool, UK. Electronic address: D.hawcutt@liv.ac.uk.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hawcutt
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000628:Aminophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D011446:Prospective Studies
chemical_list: D001993:Bronchodilator Agents; D000628:Aminophylline
keywords: Aminophylline; Dosing; PBPK modelling; Paediatric; Pharmacokinetics