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Exposure–response relationships for the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin with regard to renal risk markers
Author(s) -
Kroonen Marjolein Y. A. M.,
Koomen Jeroen V.,
Petrykiv Sergei I.,
Laverman Gozewijn D.,
Heerspink Hiddo J. L.,
Stevens Jasper
Publication year - 2020
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13976
Subject(s) - dapagliflozin , renal function , albuminuria , pharmacokinetics , creatinine , chemistry , medicine , endocrinology , urinary system , urology , type 2 diabetes , diabetes mellitus
Aims To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re‐exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter‐individual variation in response to dapagliflozin with regard to multiple renal risk markers. Methods Data were used from a crossover randomized clinical trial that assessed the albuminuria‐lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed‐effects models were used to quantify the exposure–response relationships. Results The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively ( P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 ( P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log‐transformed urinary albumin:creatinine ratio (β = −5.9, P < 0.01), body weight (β = −0.3, P < 0.01) and estimated glomerular filtration rate (β = −0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001). Conclusion An individual's exposure to dapagliflozin is consistent upon re‐exposure and correlates with pharmacodynamic response in renal risk markers.