Comparison of exposure response relationship of atrasentan between North American and Asian populations

• Published in: Diabetes, obesity & metabolism Vol. 19; no. 4; pp. 545 - 552
• Main Authors: Heerspink, Hiddo J. L., Makino, Hirofumi, Andress, Dennis, Brennan, John J., Correa‐Rotter, Ricardo, Coll, Blai, Davis, Justin W., Idler, Ken, Kohan, Donald E., Liu, Mohan, Perkovic, Vlado, Remuzzi, Giuseppe, Tobe, Sheldon W., Toto, Robert, Parving, Hans‐Henrik, de Zeeuw, Dick
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2017; Wiley Subscription Services, Inc
• Subjects: Aged; albuminuria; Albuminuria - drug therapy; Albuminuria - ethnology; Asia; Asia - ethnology; Asian Continental Ancestry Group; Asian people; atrasentan; Bilirubin - blood; Body Fluids - drug effects; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - ethnology; Diabetes Mellitus, Type 2 - urine; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - ethnology; Diabetic Nephropathies - urine; Dose-Response Relationship, Drug; Double-Blind Method; drug exposure; Endothelin Receptor Antagonists - blood; Endothelin Receptor Antagonists - pharmacokinetics; ethnic; European Continental Ancestry Group; Female; Humans; Male; Middle Aged; North America; North America - ethnology; pharmacodynamics; Plasma; Pyrrolidines - blood; Pyrrolidines - pharmacokinetics; Retention; Treatment Outcome; Weight Gain - drug effects; Weight Gain - ethnology; albuminuria; ethnic; Asia; pharmacodynamics; drug exposure; North America; atrasentan
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12851

Aims The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian 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 Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients. Results Mean albuminuria reduction in Asian, compared to North American, 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 North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P  = .024). Body surface area (β = −1.09 per m2; 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 Asian and North American populations. Conclusion The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan‐induced sodium retention.