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Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease

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Smeijer, JD, Koomen, JV, Kohan, DE, McMurray, JJV, Bakris, GL, Correa-Rotter, R, Hou, F-F, Kitzman, DW, Makino, H, Mayer, G, Nowicki, M, Perkovic, V, Rossing, P, Tobe, S, Parving, H-H, de Zeeuw, D & Heerspink, HJL 2022, 'Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease', Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.2721

APA

Smeijer, J. D., Koomen, J. V., Kohan, D. E., McMurray, J. J. V., Bakris, G. L., Correa-Rotter, R., Hou, F-F., Kitzman, D. W., Makino, H., Mayer, G., Nowicki, M., Perkovic, V., Rossing, P., Tobe, S., Parving, H-H., de Zeeuw, D., & Heerspink, H. J. L. (2022). Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.2721

CBE

Smeijer JD, Koomen JV, Kohan DE, McMurray JJV, Bakris GL, Correa-Rotter R, Hou F-F, Kitzman DW, Makino H, Mayer G, Nowicki M, Perkovic V, Rossing P, Tobe S, Parving H-H, de Zeeuw D, Heerspink HJL. 2022. Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.2721

MLA

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Author

Smeijer, J David ; Koomen, Jeroen V ; Kohan, Donald E ; McMurray, John J V ; Bakris, George L ; Correa-Rotter, Ricardo ; Hou, Fan-Fan ; Kitzman, Dalane W ; Makino, Hirofumi ; Mayer, Gert ; Nowicki, Michal ; Perkovic, Vlado ; Rossing, Peter ; Tobe, Sheldon ; Parving, Hans-Henrik ; de Zeeuw, Dick ; Heerspink, Hiddo J L. / Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease. I: Clinical Pharmacology and Therapeutics. 2022.

Bibtex

@article{bcec8edbd3f746829553a58c438c24a1,
title = "Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease",
abstract = "Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0-inf ) 41.3 ng·h/mL) or slow (atrasentan AUC0-inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.",
author = "Smeijer, {J David} and Koomen, {Jeroen V} and Kohan, {Donald E} and McMurray, {John J V} and Bakris, {George L} and Ricardo Correa-Rotter and Fan-Fan Hou and Kitzman, {Dalane W} and Hirofumi Makino and Gert Mayer and Michal Nowicki and Vlado Perkovic and Peter Rossing and Sheldon Tobe and Hans-Henrik Parving and {de Zeeuw}, Dick and Heerspink, {Hiddo J L}",
note = "This article is protected by copyright. All rights reserved.",
year = "2022",
month = jul,
day = "27",
doi = "10.1002/cpt.2721",
language = "English",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Organic anion transporter gene variants associated with plasma exposure and long-term response to atrasentan in patients with diabetic kidney disease

AU - Smeijer, J David

AU - Koomen, Jeroen V

AU - Kohan, Donald E

AU - McMurray, John J V

AU - Bakris, George L

AU - Correa-Rotter, Ricardo

AU - Hou, Fan-Fan

AU - Kitzman, Dalane W

AU - Makino, Hirofumi

AU - Mayer, Gert

AU - Nowicki, Michal

AU - Perkovic, Vlado

AU - Rossing, Peter

AU - Tobe, Sheldon

AU - Parving, Hans-Henrik

AU - de Zeeuw, Dick

AU - Heerspink, Hiddo J L

N1 - This article is protected by copyright. All rights reserved.

PY - 2022/7/27

Y1 - 2022/7/27

N2 - Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0-inf ) 41.3 ng·h/mL) or slow (atrasentan AUC0-inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.

AB - Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0-inf ) 41.3 ng·h/mL) or slow (atrasentan AUC0-inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.

U2 - 10.1002/cpt.2721

DO - 10.1002/cpt.2721

M3 - Journal article

C2 - 35892316

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

ER -

ID: 79928903