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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

1
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
2
Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD, USA.
3
Diabetes Medical Department, AstraZeneca GmbH, Wedel, Germany.
4
AUF DER BULT, ChildrenĀ“s and Youth Hospital, Hannover, Germany.
5
M&S Decisions, Moscow, Russia.

Abstract

AIMS:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
31077437
DOI:
10.1111/bcp.13981

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