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Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth
1Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, England, UK.
Insights
Mathematical modeling of insulin-like growth factor-1 (IGF-1) in children with Crohn's disease helps determine safe dosing. This approach normalizes IGF-1 levels, reducing cancer risk associated with high concentrations.
Area of Science:
- Pediatric Endocrinology
- Gastroenterology
- Pharmacokinetics
Background:
- Children with Crohn's disease experience poor growth due to inflammation impacting insulin-like growth factor-1 (IGF-1) response.
- Current treatment limitations exist for normalizing growth velocity in all children with Crohn's disease.
- Understanding IGF-1 kinetics is crucial to avoid potential cancer risks linked to prolonged high IGF-1 levels.
Purpose of the Study:
- To develop a mathematical model for IGF-1 kinetics in children with Crohn's disease.
- To establish dosing regimens for IGF-1 that normalize concentrations without increasing cancer risk.
- To investigate the impact of disease activity on IGF-1 synthesis and clearance.
Main Methods:
- A pharmacokinetic intervention study involving 8 children with active Crohn's disease.
- Administration of subcutaneous recombinant human IGF-1 (rhIGF-1) in single and twice-daily doses.
- Development of a mathematical model (dAc/dt=Ksyn - Kout×Ac+Ka×As) to describe IGF-1 pharmacokinetics.
Main Results:
- Subcutaneous rhIGF-1 administration significantly increased circulating IGF-1 concentrations.
- Twice-daily dosing effectively maintained normalized IGF-1 levels.
- Disease activity was found to significantly reduce endogenous IGF-1 synthesis (Ksyn, p<0.001).
Conclusions:
- Mathematical modeling allows for personalized IGF-1 dosing strategies in pediatric Crohn's disease.
- Age, weight, and disease activity scaling can optimize rhIGF-1 dosage.
- Over 95% of patients can achieve normalized IGF-1 levels below a cancer-associated threshold (+2.5 SDs).
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 microg/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 (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.
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