title: Comparison of exposure response relationship of atrasentan between North American and Asian populations.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J L
authors.initials: HJ
authors.lastname: Heerspink
authors.affiliation: Okayama University Graduate School of Medicine, Okayama City, Okayama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: Dennis
authors.initials: D
authors.lastname: Andress
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: John J
authors.initials: JJ
authors.lastname: Brennan
authors.affiliation: Department of Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Correa-Rotter
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: Blai
authors.initials: B
authors.lastname: Coll
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Davis
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: Ken
authors.initials: K
authors.lastname: Idler
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.affiliation: Renal Clinical Development, AbbVie, Chicago, Illinois.
authors.forename: Mohan
authors.initials: M
authors.lastname: Liu
authors.affiliation: George Institute for Global Health, University of Sydney, Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Azienda Ospedaliera Papa Giovanni XXIII and IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: Department of Hypertension and Nephrology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Sheldon W
authors.initials: SW
authors.lastname: Tobe
authors.affiliation: Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Robert
authors.initials: R
authors.lastname: Toto
authors.affiliation: Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000188:drug therapy / Q000208:ethnology; D001208:Asia / Q000208:ethnology; D044466:Asian People; D000077868:Atrasentan; D001663:Bilirubin / Q000097:blood; D001826:Body Fluids / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000208:ethnology / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000208:ethnology / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009656:North America / Q000208:ethnology; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects / Q000208:ethnology; D044465:White People
chemical_list: D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D001663:Bilirubin; D000077868:Atrasentan
keywords: 
  Asia; 
  North America; albuminuria; atrasentan; drug exposure; ethnic; pharmacodynamics