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), baseline24-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.
RCT Entities:
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.
Authors: Marjolein Y A M Kroonen; Jeroen V Koomen; Sergei I Petrykiv; Gozewijn D Laverman; Hiddo J L Heerspink; Jasper Stevens Journal: Diabetes Obes Metab Date: 2020-02-17 Impact factor: 6.577
Authors: Jennifer R Donnan; Catherine A Grandy; Eugene Chibrikov; Carlo A Marra; Kris Aubrey-Bassler; Karissa Johnston; Michelle Swab; Jenna Hache; Daniel Curnew; Hai Nguyen; John-Michael Gamble Journal: BMJ Open Date: 2019-02-01 Impact factor: 2.692