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

Autor: van der Aart-van der Beek AB; Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.; Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands., Koomen JV; Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands., Dekkers CCJ; Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands., Barbour SJ; Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada., Boulton DW; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, USA., Gansevoort RT; Department of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands., Greasley PJ; Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Abdul Gafor AH; Department of Medicine, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia., Laverman GD; Department of Internal Medicine, ZGT Hospital, Almelo and Hengelo, The Netherlands., Li Q; The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia., Lim SK; Division of Nephrology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Stevens J; Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands., Vervloet MG; Department of Nephrology and Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands., Singh S; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada., Cattran DC; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada., Reich HN; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada., Cherney DZI; Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada., Heerspink HJL; 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.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2021 Apr; Vol. 60 (4), pp. 517-525. Date of Electronic Publication: 2021 Feb 15.
DOI: 10.1007/s40262-020-00956-1
Abstrakt: 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.
Databáze: MEDLINE
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