Comparison of the exposure–response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus. Issue 7 (13th June 2016)

• Record Type: Journal Article
• Authors: Parkinson, J.; Tang, W.; Johansson, C‐C.; Boulton, D. W.; Hamrén, B.
• Is Part Of: Diabetes, obesity & metabolism. Volume 18:Issue 7(2016)
• Page Start: 685
• Page End: 692
• Publication Date: 2016-06-13
• Subjects: covariates -- dapagliflozin -- exposure–response -- paediatric -- type 2 diabetes mellitus; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.12647
• Languages: English
• ISSNs: 1462-8902

Abstract

Abstract : Aims: To quantitatively compare the exposure–response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus (T2DM) and to assess the potential impact of covariate effects. Methods: Data from three clinical studies of single‐dose (2.5, 5 and 10 mg), orally administered dapagliflozin in adult (NCT00162305, NCT00538174) and paediatric (NCT01525238) patients with T2DM were analysed to examine the relationship between dapagliflozin exposure (area under concentration–time curve) and response [24‐h urinary glucose excretion (UGE)] using a sigmoidal maximum effect model. Baseline fasting plasma glucose (FPG), estimated glomerular filtration rate (eGFR), baseline 24‐h UGE, sex and race were evaluated as covariates. Results: Data from 63 predominantly white or Asian (92.4%) adult and 20 paediatric (45.8% white; 45.8% black) patients were included. The model appeared robust, with predictions fitting well with observed data. Baseline eGFR, FPG and sex were significant covariates in both populations; race was a significant covariate in the paediatric population only. Model‐predicted UGE response was higher in paediatric (47.4, 67.5 and 85.9 g/24 h for 2.5, 5 and 10 mg) than in adult (31.2, 43.5 and 54.3 g/24 h for 2.5, 5 and 10 mg) patients, which may be associated with the higher eGFR values in paediatric patients. Conclusions: After a single oral dose of dapagliflozin, adult and paediatric patients with T2DM had similar exposure‐response relationships after accounting for significant covariates. These results support the planned dosage strategy for a phase III dapagliflozin safety and efficacy study in paediatric patients with T2DM, for whom treatment options are currently limited.