Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: A pharmacokinetic study

Abstract

Objectives: 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. Design: Pharmacokinetic intervention study. Setting: Tertiary paediatric gastroenterology unit. Participants: 8 children (M:F; 4:4) entered the study. All completed: 5 South Asian British; 2 White British; 1 African British. Inclusion criteria: 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 <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.