Key result
Atrasentan 0.75 mg/d reduces UACR ~34% with minimal sodium retention versus the 1.25 mg/d dose.
Why the study?
The optimal dose of atrasentan balancing maximal albuminuria reduction and minimal sodium retention in patients with type 2 diabetes and kidney disease was unknown.
What is the optimal dose of atrasentan to maximize albuminuria reduction while minimizing sodium retention in patients with type 2 diabetes and kidney disease?
What is the optimal dose of atrasentan to maximize albuminuria reduction while minimizing sodium retention in patients with type 2 diabetes and kidney disease?
Absolute Event Rate: 34% vs 40.1%
p-value: p=<.01
Atrasentan 0.75 mg/d provides the optimal balance of maximizing albuminuria reduction while minimizing sodium retention in patients with diabetic kidney disease.
Supports 0.75 mg/d as preferred atrasentan dose in diabetic kidney disease; extends RCT dose-optimization data for endothelin antagonists.
This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR-JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).
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Koomen et al. (2018) studied Type 2 diabetes and kidney disease (n=161). Atrasentan vs. 1.25 mg/d was evaluated on Mean urinary albumin-to-creatinine ratio (UACR) reduction (p=<.01). Atrasentan 0.75 mg/d provided optimal kidney protection with a 34.0% mean UACR reduction and minimal sodium retention (0.9 kg bodyweight increase) compared to the 1.25 mg/d dose.