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

van der Aart-van der Beek AB 1 , Koomen JV 1 , Dekkers CCJ 1 , Barbour SJ 2 , Boulton DW 3 , Gansevoort RT 4 Show all authors , Greasley PJ 5 , Abdul Gafor AH 6 , Laverman GD 7 , Li Q 8 , Lim SK 9 , Stevens J 1 , Vervloet MG 10 , Singh S 11 , Cattran DC 11 , Reich HN 11 , Cherney DZI 11 , Heerspink HJL 12

Affiliations 

  • 1 Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands
  • 2 Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
  • 3 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, USA
  • 4 Department of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
  • 5 Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • 6 Department of Medicine, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
  • 7 Department of Internal Medicine, ZGT Hospital, Almelo and Hengelo, The Netherlands
  • 8 The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia
  • 9 Division of Nephrology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 10 Department of Nephrology and Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
  • 11 Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada
  • 12 Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands. h.j.lambers.heerspink@umcg.nl
Clin Pharmacokinet, 2021 04;60(4):517-525.
PMID: 33587286 DOI: 10.1007/s40262-020-00956-1

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 

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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