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

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 <–2 SD score. Exclusion criteria: closed epiphyses; corticosteroids within 3 months; neoplasia or known hypersensitivity to recombinant human IGF-1 (rhIGF-1). INTERVENTIONS: 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. PRIMARY OUTCOME: Significant increase in circulating IGF-1. SECONDARY OUTCOMES: Incidence of side effects of IGF-1. A mathematical model of circulating IGF-1 (A(c)) was developed to include parameters of endogenous synthesis (K(syn)); exogenous uptake (K(a)) from the subcutaneous dose (A(s)): and IGF-1 clearance: where dA(c)/dt=K(syn) − K(out)×A(c)+K(a)×A(s). RESULTS: Subcutaneous IGF-1 increased concentrations, which were maintained on twice daily doses. In covariate analysis, disease activity reduced K(syn) (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.