Hiddo J L Heerspink1, Hirofumi Makino2, Dennis Andress3, John J Brennan3, Ricardo Correa-Rotter4, Blai Coll3, Justin W Davis3, Ken Idler3, Donald E Kohan5, Mohan Liu3, Vlado Perkovic6, Giuseppe Remuzzi7, Sheldon W Tobe8, Robert Toto9, Hans-Henrik Parving10, Dick de Zeeuw1. 1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Okayama University Graduate School of Medicine, Okayama City, Okayama, Japan. 3. Renal Clinical Development, AbbVie, Chicago, Illinois. 4. Department of Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico. 5. Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah. 6. George Institute for Global Health, University of Sydney, Sydney, Australia. 7. Azienda Ospedaliera Papa Giovanni XXIII and IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy. 8. Department of Hypertension and Nephrology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 9. Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas. 10. Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
Abstract
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.
RCT Entities:
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.
Authors: Jeroen V Koomen; Jasper Stevens; George Bakris; Ricardo Correa-Rotter; Fan Fan Hou; Dalane W Kitzman; Donald Kohan; Hirofumi Makino; John J V McMurray; Hans-Henrik Parving; Vlado Perkovic; Sheldon W Tobe; Dick de Zeeuw; Hiddo J L Heerspink Journal: Diabetes Obes Metab Date: 2020-11-26 Impact factor: 6.577