Dapagliflozin Pharmacokinetics Is Similar in Adults With Type 1 and Type 2 Diabetes Mellitus

Johanna Melin, Weifeng Tang, Dinko Rekić, Bengt Hamrén, Robert C Penland, David W Boulton, Joanna Parkinson, Johanna Melin, Weifeng Tang, Dinko Rekić, Bengt Hamrén, Robert C Penland, David W Boulton, Joanna Parkinson

Abstract

Dapagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) and is approved in Japanese patients with type 1 diabetes mellitus (T1DM) with inadequate glycemic control. The objectives of this work were to characterize 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. Population PK analysis was performed using a nonlinear mixed-effect modeling approach. The analysis included 5793 dapagliflozin plasma concentrations from 1150 adult patients with T1DM (global population), who were on routine insulin therapy, collected from 1 phase 2 (NCT01498185) and 2 phase 3 (DEPICT-1, NCT02268214; DEPICT-2, NCT02460978) studies. Covariate effects were investigated using stepwise covariate modeling. Model-derived area under the concentration-time curve (AUC) in patients with T1DM was compared to AUC in patients with T2DM (using data from historical dapagliflozin studies). The final 2-compartmental model adequately described the dapagliflozin concentrations in patients with T1DM. The estimated apparent clearance was 20.5 L/h. Renal function (measured as estimated glomerular filtration rate), sex, and body weight were identified as covariates, where patients with better renal function, male patients, and heavier patients had lower dapagliflozin systemic exposure. Among the covariates studied, none of the covariates affected dapagliflozin systemic exposure >1.4-fold compared to a reference individual and were therefore deemed to be not clinically relevant. Dapagliflozin systemic exposure was comparable between patients with T1DM and T2DM.

Keywords: SGLT2 inhibitor; dapagliflozin; pharmacokinetics; type 1 diabetes; type 2 diabetes.

Conflict of interest statement

All authors are employees of AstraZeneca and own AstraZeneca stock.

© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Prediction‐corrected visual predictive check stratified by study. Lines: 10th, 50th, and 90th percentiles of observed data. Shaded areas: 95% confidence interval around 10th, 50th, and 90th percentiles of simulated data (n = 1000). Circles: Observations. For steady‐state observations, time after last once‐daily dose is plotted.
Figure 2
Figure 2
Forest plot showing covariate effect of the full dapagliflozin covariate model for model‐predicted AUC. The solid vertical line corresponds to the reference individual: White male with body weight of 78.7 kg and eGFR of 88.6 mL/min/1.73 m2. The symbols represent the median model‐predicted AUC ratio, and the whiskers represent the 95% confidence interval. “Other” race corresponds to Other, Native Hawaiian/Other Pacific Islander. AUC, area under the concentration‐time curve; eGFR, estimated glomerular filtration rate.
Figure 3
Figure 3
Dose‐normalized dapagliflozin AUC in T1DM stratified on different covariates. “Other” race corresponds to Other, Native Hawaiian/Other Pacific Islander. Vertical line corresponds to median, boxes represent the interquartile range, whiskers correspond to minimum and maximum (lowest and highest data point excluding outliers, respectively), and datapoints correspond to outliers. AUC, area under the concentration‐time curve; eGFR, estimated glomerular filtration rate; T1DM, type 1 diabetes mellitus.
Figure 4
Figure 4
Dose‐normalized dapagliflozin AUC in patients with T1DM vs patients with T2DM. Vertical line corresponds to median, boxes represent the interquartile range, whiskers correspond to minimum and maximum (lowest and highest data point excluding outliers, respectively), and datapoints correspond to outliers. AUC, area under the concentration‐time curve; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

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