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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
Author(s) -
Smeijer J. David,
Koomen Jeroen V.,
Kohan Donald E.,
McMurray John J. V.,
Bakris George L.,
CorreaRotter Ricardo,
Hou FanFan,
Kitzman Dalane W.,
Makino Hirofumi,
Mayer Gert,
Nowicki Michal,
Perkovic Vlado,
Rossing Peter,
Tobe Sheldon,
Parving HansHenrik,
Zeeuw Dick,
Heerspink Hiddo J. L.
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2721
Subject(s) - transporter , diabetes mellitus , organic anion transporter 1 , kidney disease , kidney , pharmacology , medicine , plasma concentration , gene , chemistry , endocrinology , biochemistry
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 m 2 , 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 (AUC 0−inf ) 41.3 ng·h/mL) or slow (atrasentan AUC 0−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.