Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.
Clin Pharmacol Ther
; 109(6): 1631-1638, 2021 06.
Article
in En
| MEDLINE
| ID: mdl-33338269
ABSTRACT
Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI) 0.28-0.85) for kidney events and 1.13 (95% CI 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 2
/
Diabetic Nephropathies
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Atrasentan
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Heart Failure
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Kidney Failure, Chronic
Type of study:
Clinical_trials
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Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Clin Pharmacol Ther
Year:
2021
Document type:
Article
Affiliation country:
Países Bajos