Dapagliflozin pharmacokinetics is similar in adults with type 1 and type
2 diabetes mellitus
Abstract
Aim: Dapagliflozin improves glycaemic control in patients with type 2
diabetes mellitus (T2DM) and is approved in European and Japanese
patients with type 1 diabetes mellitus (T1DM) with inadequate glycaemic
control. The objectives of this work were to characterise the
dapagliflozin pharmacokinetics (PK) in patients with T1DM, assess the
influence of covariates on dapagliflozin PK, and compare dapagliflozin
systemic exposure between patients with T1DM and T2DM. Methods:
Population PK analysis was performed using a non-linear mixed-effect
modelling approach. The analysis included 5,793 dapagliflozin plasma
concentrations from 1,150 adult patients with T1DM, collected from one
phase 2 (NCT01498185) and two phase 3 studies (DEPICT-1, NCT02268214;
DEPICT-2, NCT02460978). Covariate effects were investigated using
stepwise covariate modelling. Model-derived area under the
concentration-time curve (AUC) was compared with AUC in patients with
T2DM. Results: The final two-compartmental model adequately described
the dapagliflozin concentrations in patients with T1DM. The estimated
apparent clearance was 20.5 L/h. Model-predicted systemic exposure for 5
mg and 10 mg of dapagliflozin indicated dose-proportionality and was
comparable between patients with T1DM and T2DM. The identified covariate
relationships showed that patients with better renal function (measured
as estimated glomerular filtration rate), males, and heavier patients
had lower dapagliflozin systemic exposure. Among the covariates studied,
no covariates affected dapagliflozin systemic exposure to a clinically
relevant extent. Conclusions: Dapagliflozin PK in patients with T1DM was
adequately described by the population PK model and no clinically
relevant covariates were identified. Dapagliflozin systemic exposure was
comparable between patients with T1DM and T2DM. NCT01498185,
NCT02268214, NCT02460978