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- Title
Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight.
- Authors
Koomen, Jeroen V.; Stevens, Jasper; Mostafa, Nael M.; Parving, Hans‐Henrik; de Zeeuw, Dick; Heerspink, Hiddo J. L.
- Abstract
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).
- Subjects
ALBUMINURIA; BODY weight; DIABETIC nephropathies; ENDOTHELIN receptors; PHARMACODYNAMICS; PHARMACOKINETICS; CREATININE; SODIUM in the body
- Publication
Diabetes, Obesity & Metabolism, 2018, Vol 20, Issue 8, p2019
- ISSN
1462-8902
- Publication type
Article
- DOI
10.1111/dom.13312