title: Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: a pharmacokinetic study.
abstract: OBJECTIVE
  Children with Crohn's disease grow poorly, and inflammation depresses the response of insulin-like growth factor-1 (IGF-1) to growth hormone. Correcting the inflammation normalises growth velocity; however, removing inflammation cannot be achieved in all children. Our lack of understanding of IGF-1 kinetics has hampered its use, particularly as high IGF-1 concentrations over long periods may predispose to colon cancer. We hypothesised that mathematical modelling of IGF-1 would define dosing regimes that return IGF-1 concentrations into the normal range, without reaching values that risk cancer.
  
  
  METHODS
  Pharmacokinetic intervention study.
  
  
  METHODS
  Tertiary paediatric gastroenterology unit.
  
  
  METHODS
  8 children (M:F; 4:4) entered the study. All completed: 5 South Asian British; 2 White British; 1 African British.
  
  
  METHODS
  Children over 10 years with active Crohn's disease (C reactive protein >10 mg/l or erythrocyte sedimentation rate >25 mm/h) and height velocity <-2 SD score.
  
  
  METHODS
  closed epiphyses; corticosteroids within 3 months; neoplasia or known hypersensitivity to recombinant human IGF-1 (rhIGF-1).
  
  
  METHODS
  Subcutaneous rhIGF-1 (120 μg/kg) per dose over two admissions: the first as a single dose and the second as twice daily doses over 5 days.
  
  
  METHODS
  Significant increase in circulating IGF-1.
  
  
  RESULTS
  Incidence of side effects of IGF-1. A mathematical model of circulating IGF-1 (Ac) was developed to include parameters of endogenous synthesis (Ksyn); exogenous uptake (Ka) from the subcutaneous dose (As): and IGF-1 clearance: where dAc/dt=Ksyn - Kout×Ac+Ka×As.
  
  
  RESULTS
  Subcutaneous IGF-1 increased concentrations, which were maintained on twice daily doses. In covariate analysis, disease activity reduced Ksyn (p<0.001). Optimal dosing was derived from least squares regression fitted to a dataset of 384 Crohn's patients, with model parameters assigned by simulation.
  
  
  CONCLUSIONS
  By using age, weight and disease activity scaling in IGF-1 dosing, over 95% of children will have normalised IGF-1 concentrations below +2.5 SDs of the normal population mean, a level not associated with cancer risk.
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, England, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rao
authors.forename: J F
authors.initials: JF
authors.lastname: Standing
authors.forename: S
authors.initials: S
authors.lastname: Naik
authors.forename: M O
authors.initials: MO
authors.lastname: Savage
authors.forename: I R
authors.initials: IR
authors.lastname: Sanderson
keywords: adolescent; height; inflammatory bowel disease; insulin-like growth factor-1; pharmacokinetics