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

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Koomen, Jeroen V ; Stevens, Jasper ; Mostafa, Nael M ; Parving, Hans-Henrik ; de Zeeuw, Dick ; Heerspink, Hiddo J L. / Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight. In: Diabetes, Obesity and Metabolism. 2018 ; Vol. 20, No. 8. pp. 2019-2022.

Bibtex

@article{b4d0f97f3404406cb347e78ce1f4936d,
title = "Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight",
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).",
keywords = "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",
author = "Koomen, {Jeroen V} and Jasper Stevens and Mostafa, {Nael M} and Hans-Henrik Parving and {de Zeeuw}, Dick and Heerspink, {Hiddo J L}",
note = "{\circledC} 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.",
year = "2018",
month = "8",
doi = "10.1111/dom.13312",
language = "English",
volume = "20",
pages = "2019--2022",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight

AU - Koomen, Jeroen V

AU - Stevens, Jasper

AU - Mostafa, Nael M

AU - Parving, Hans-Henrik

AU - de Zeeuw, Dick

AU - Heerspink, Hiddo J L

N1 - © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

PY - 2018/8

Y1 - 2018/8

N2 - 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).

AB - 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).

KW - Albuminuria/prevention & control

KW - Angiotensin Receptor Antagonists/therapeutic use

KW - Angiotensin-Converting Enzyme Inhibitors/therapeutic use

KW - Atrasentan/administration & dosage

KW - Biological Variation, Population

KW - Biomarkers/urine

KW - Body Weight/drug effects

KW - Diabetes Mellitus, Type 2/complications

KW - Diabetic Nephropathies/blood

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Drug Resistance

KW - Drug Therapy, Combination/adverse effects

KW - Endothelin A Receptor Antagonists/administration & dosage

KW - Humans

KW - Metabolic Clearance Rate/drug effects

KW - Renal Elimination/drug effects

KW - Renal Insufficiency/complications

KW - Severity of Illness Index

KW - Sodium/metabolism

U2 - 10.1111/dom.13312

DO - 10.1111/dom.13312

M3 - Journal article

VL - 20

SP - 2019

EP - 2022

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 8

ER -

ID: 56465617