Evaluation of the Pharmacokinetics and Exposure–Response Relationship of Dapagliflozin in Patients without Diabetes and with Chronic Kidney Disease

Abstract

Background and Objective Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes. Methods Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m 2 and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response. Results Plasma concentrations ( n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m 2 , median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7–12.7) L/h and 44.9 (95% confidence interval 39.0–50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th–97.5th percentiles: 434.0–1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio ( β = − 2.8%, p = 0.01), glomerular filtration rate ( β = − 0.5 mL/min/1.73 m 2 , p < 0.01) and systolic blood pressure ( β = − 0.4 mmHg, p = 0.03). Conclusions The dapagliflozin plasma concentration–time profile in patients with non-diabetic kidney disease appears similar to the profile of patients with diabetic kidney disease described in the literature. Furthermore, the plasma exposure was associated with changes in risk markers for kidney disease.

Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin–Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity

“…Reducing both renal and non–renal elimination of key TGT components likely changes the in vivo exposure of these components. The plasma exposure of five key TGT components (TPL, WFG, WFT, WFD, and WFR) and the tissue contents of six key TGT components (TPL, WA, WFG, WFT, WFD, and WFR) in the heart, liver, spleen, lung, kidney, and brain increased significantly after single–dose TGT administration in NS rats ( Figures 5 , 6 and Table 1 ), consistent with previous reports that the plasma exposure of certain drugs increased when kidney function declined ( Albrecht et al, 2017 ; van der Aart-van der Beek et al, 2021 ). Furthermore, the cumulative exposure of four key TGT components (TPL, WFG, WFT, and WFD) in the kidney and liver also increased after multi–dose TGT administration in NS rats, particularly advanced–stage NS rats ( Figure 7 ).…”

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

“…Results of a mixed-effects model studying PK and exposure-response of dapagliflozin in patients with CKD reported that every 100 ng • h/mL rise in dapagliflozin exposure was associated with a decrease in eGFR (β = −0.5 mL/min/1.73 m 2 ; P < .01), thereby supporting our findings. 3 The popPK model characterizing dapagliflozin PK in patients with HFrEF also found that the systemic exposure was 1.5-and 1.8-fold higher in patients with reduced kidney function (eGFR of 45-59 and 30-44 mL/min/1.73 m 2 , respectively) than in those with a normal eGFR (≥90 mL/min/1.73 m 2 ). 21 The 10-mg once-daily dose of dapagliflozin has been deemed safe and is recommended for patients with CKD, T2DM, and HFrEF.…”

“…Dapagliflozin is a highly potent, selective, and reversible sodium-glucose cotransporter 2 inhibitor, developed as an oral antihyperglycemic drug to lower plasma glucose and glycated hemoglobin by blocking renal glucose reabsorption in the proximal tubule, thereby improving urinary glucose excretion. [1][2][3] Dapagliflozin, taken once daily (up to 10 mg), has been approved by the US Food and Drug Administration (FDA), by the European Medicines Agency, and in Japan, as well as numerous countries worldwide, for the treatment of type 2 diabetes mellitus (T2DM) in adults, and it is also approved for the treatment of type 1 diabetes mellitus (T1DM) in Japan. [4][5][6][7] However, the benefits of dapagliflozin extend beyond achieving glycemic control to reducing the risk of renal, cardiovascular, and mortality end points in patients with and without T2DM, as reported by the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) and Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) clinical trials, respectively.…”

“…Dapagliflozin is a highly potent, selective, and reversible sodium‐glucose cotransporter 2 inhibitor, developed as an oral antihyperglycemic drug to lower plasma glucose and glycated hemoglobin by blocking renal glucose reabsorption in the proximal tubule, thereby improving urinary glucose excretion 1–3 . Dapagliflozin, taken once daily (up to 10 mg), has been approved by the US Food and Drug Administration (FDA), by the European Medicines Agency, and in Japan, as well as numerous countries worldwide, for the treatment of type 2 diabetes mellitus (T2DM) in adults, and it is also approved for the treatment of type 1 diabetes mellitus (T1DM) in Japan 4–7…”

Exposure–Response Analysis of the Sodium–Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes

“…The underlying mechanisms of this individual variation in response to SGLT2 inhibition are incompletely understood. Systemic exposure to several SGLT2 inhibitors is variable between patients and related to responses in metabolic variables including glycemic control, body weight, and systolic blood pressure [ 17 , 18 , 19 , 20 ]. Less is known about the association between exposure to SGLT2 inhibition and responses in kidney variables including kidney hemodynamic changes.…”