Evaluation of the Pharmacokinetics of Dapagliflozin in Patients With Chronic Kidney Disease With or Without Type 2 Diabetes Mellitus.

Evidence shows that SGLT2 inhibitors, such as dapagliflozin, can delay the progressive decline of kidney function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We used a population pharmacokinetics (popPK) model to characterize the pharmacokinetics of dapagliflozin in patients with CKD and compare dapagliflozin systemic exposure in different populations, such as CKD with or without T2DM and T2DM without CKD. A two-compartmental popPK model was developed from a previous popPK model. The final popPK model was based on 9715 dapagliflozin plasma concentrations from 3055 patients included in clinical studies involving adults with CKD with or without T2DM, adults with T2DM, healthy subjects, and pediatric patients with T2DM. Overall, the apparent clearance for patients treated with dapagliflozin was 21.6 L/h, similar to previous estimates in adults with T2DM and healthy subjects (22.9 L/h). Model-derived area under the plasma concentration-time curve (AUC) was not meaningfully different between CKD patients with and without T2DM. Median AUC was 1.6-fold higher in adult CKD patients with T2DM compared with adult T2DM patients without CKD. Compared with patients with normal kidney function (eGFR ≥90 mL/min/1.73 m 2 ), median AUC was 2.4-fold higher in CKD patients (with/without T2DM) with eGFR 15-29 mL/min/1.73 m 2 owing to decreased renal clearance of dapagliflozin. A higher AUC was observed in patients with a higher age or lower body weight but was not considered clinically relevant. This popPK model adequately described dapagliflozin pharmacokinetics and found that systemic exposure in patients with CKD was consistent, irrespective of T2DM status. This article is protected by copyright. All rights reserved.