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Comparison of exposure response relationship of atrasentan between North American and Asian populations.
- Source :
-
Diabetes, obesity & metabolism [Diabetes Obes Metab] 2017 Apr; Vol. 19 (4), pp. 545-552. Date of Electronic Publication: 2017 Jan 27. - Publication Year :
- 2017
-
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.<br />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.<br />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 m <superscript>2</superscript> ; 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.<br />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.<br /> (© 2016 John Wiley & Sons Ltd.)
- Subjects :
- Aged
Albuminuria drug therapy
Albuminuria ethnology
Asia ethnology
Asian People
Atrasentan
Bilirubin blood
Body Fluids drug effects
Diabetes Mellitus, Type 2 ethnology
Diabetes Mellitus, Type 2 urine
Diabetic Nephropathies ethnology
Diabetic Nephropathies urine
Dose-Response Relationship, Drug
Double-Blind Method
Endothelin Receptor Antagonists blood
Female
Humans
Male
Middle Aged
North America ethnology
Pyrrolidines blood
Treatment Outcome
Weight Gain drug effects
Weight Gain ethnology
White People
Diabetes Mellitus, Type 2 complications
Diabetic Nephropathies drug therapy
Endothelin Receptor Antagonists pharmacokinetics
Pyrrolidines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1463-1326
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes, obesity & metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 27981738
- Full Text :
- https://doi.org/10.1111/dom.12851