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Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight

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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).

Original languageEnglish
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number8
Pages (from-to)2019-2022
Number of pages4
ISSN1462-8902
DOIs
Publication statusPublished - Aug 2018

    Research areas

  • Albuminuria/prevention & control, Angiotensin Receptor Antagonists/therapeutic use, Angiotensin-Converting Enzyme Inhibitors/therapeutic use, Atrasentan/administration & dosage, Biological Variation, Population, Biomarkers/urine, Body Weight/drug effects, Diabetes Mellitus, Type 2/complications, Diabetic Nephropathies/blood, Dose-Response Relationship, Drug, Double-Blind Method, Drug Resistance, Drug Therapy, Combination/adverse effects, Endothelin A Receptor Antagonists/administration & dosage, Humans, Metabolic Clearance Rate/drug effects, Renal Elimination/drug effects, Renal Insufficiency/complications, Severity of Illness Index, Sodium/metabolism

ID: 56465617