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Br J Clin Pharmacol. 2019 May 11. doi: 10.1111/bcp.13981. [Epub ahead of print]

Comparison of pharmacokinetics and the exposure-response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus.

Author information

Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD, USA.
Diabetes Medical Department, AstraZeneca GmbH, Wedel, Germany.
AUF DER BULT, ChildrenĀ“s and Youth Hospital, Hannover, Germany.
M&S Decisions, Moscow, Russia.



To quantitatively compare pharmacokinetics (PK) and the exposure-response relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM).


Data from two clinical studies for dapagliflozin were analysed using a non-linear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-h urinary glucose excretion [UGE]) were characterised. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model. 24-h median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates.


A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The exposure-response relationship was best described by a sigmoidal maximal effect model with 24-h median blood glucose and eGFR as significant covariates on Emax. In accordance with the observed data, model-predicted UGE response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-h median blood glucose in this trial.


Dapagliflozin PK and exposure-response relationship were similar in the two analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.


covariates; dapagliflozin; exposure-response; paediatric; pharmacokinetics; type 1 diabetes mellitus


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