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

Annemarie B van der Aart-van der Beek, Jeroen V Koomen, Claire C J Dekkers, Sean J Barbour, David W Boulton, Ron T Gansevoort, Peter J Greasley, Abdul Halim Abdul Gafor, Gozewijn D Laverman, Qiang Li, Soo Kun Lim, Jasper Stevens, Marc G Vervloet, Sunita Singh, Daniel C Cattran, Heather N Reich, David Z I Cherney, Hiddo J L Heerspink*

*Corresponding author for this work

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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 m2 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 m2, 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 m2, 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.

Original languageEnglish
Number of pages9
JournalClinical Pharmacokinetics
Early online date15-Feb-2021
DOIs
Publication statusPublished - 15-Feb-2021

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