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Comparison of exposure response relationship of atrasentan between N orth A merican and A sian populations
Author(s) -
Heerspink Hiddo J. L.,
Makino Hirofumi,
Andress Dennis,
Brennan John J.,
CorreaRotter Ricardo,
Coll Blai,
Davis Justin W.,
Idler Ken,
Kohan Donald E.,
Liu Mohan,
Perkovic Vlado,
Remuzzi Giuseppe,
Tobe Sheldon W.,
Toto Robert,
Parving HansHenrik,
de Zeeuw Dick
Publication year - 2017
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.12851
Subject(s) - albuminuria , pharmacodynamics , placebo , medicine , urology , type 2 diabetes , diabetic nephropathy , endocrinology , pharmacology , chemistry , diabetes mellitus , pharmacokinetics , pathology , alternative medicine
Aims The selective endothelin ( ET ) A receptor antagonist atrasentan has been shown to lower albuminuria in N orth A merican and A sian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between N orth A merican and A sian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. Materials and methods Two 12‐week double‐blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in A sians ( N = 77) and N orth A mericans ( N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients. Results Mean albuminuria reduction in Asian, compared to N orth A merican, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d ( P = .44) and −48.0% vs −28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between N orth A merican and A sian populations. Atrasentan plasma concentrations were higher in A sians compared to N orth A mericans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = −1.09 per m 2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/ dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between A sian and N orth A merican populations. Conclusion The higher exposure and albuminuria reduction of atrasentan in A sian patients is not associated with more fluid retention, suggesting that A sian patients are less sensitive to atrasentan‐induced sodium retention.