Document Detail


Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: a pharmacokinetic study.
MedLine Citation:
PMID:  23793696     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
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 (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:
A Rao; J F Standing; S Naik; M O Savage; I R Sanderson
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Publication Detail:
Type:  Journal Article     Date:  2013-05-28
Journal Detail:
Title:  BMJ open     Volume:  3     ISSN:  2044-6055     ISO Abbreviation:  BMJ Open     Publication Date:  2013  
Date Detail:
Created Date:  2013-06-24     Completed Date:  2013-06-25     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  101552874     Medline TA:  BMJ Open     Country:  England    
Other Details:
Languages:  eng     Pagination:  -     Citation Subset:  -    
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Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
G1002305//Medical Research Council

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