Comparison of the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus.
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.



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.



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.



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.
AstraZeneca Gothenburg, Mölndal, Sweden.
J
J
Parkinson
AstraZeneca, Gaithersburg, MD, USA.
W
W
Tang
AstraZeneca Gothenburg, Mölndal, Sweden.
C-C
CC
Johansson
AstraZeneca, Gaithersburg, MD, USA.
D W
DW
Boulton
AstraZeneca Gothenburg, Mölndal, Sweden.
B
B
Hamrén
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C529054:dapagliflozin
covariates; dapagliflozin; exposure–response; paediatric; type 2 diabetes mellitus