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 (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.

中文翻译：

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有机阴离子转运蛋白基因变异与糖尿病肾病患者的血浆暴露和阿曲生坦的长期反应相关

内皮素受体拮抗剂阿曲生坦的血浆暴露因人而异，与肾保护作用和心力衰竭风险相关。我们检查了遗传多态性对阿特拉生坦血浆暴露和药效学效应的影响。我们对阿曲生坦糖尿病肾病研究 (SONAR) 试验进行了一项子研究，该试验招募了患有 2 型糖尿病和慢性肾病（估计肾小球滤过率：25–75 mL/min/1.73 m ^{2 ）的成年人}，以及尿白蛋白与肌酐的比率为 300–5,000 mg/g）。确定了预先指定的膜转运蛋白、代谢酶和内皮素 1 肽的单核苷酸多态性 (SNP)。使用 Cox 比例风险回归模型评估基因型、atrasentan 血浆暴露和 atrasentan 对预先指定的肾脏和心力衰竭住院 (HHF) 结果的影响之间的关联。在随机分配的 3,668 名患者中，2,329 名 (63.5%) 同意进行基因型分析。编码肝脏有机阴离子转运蛋白 1B1 (OATP1B1) 的 SLCO1B1 基因（rs4149056 和 rs2306283）中的两个 SNP 显示出与阿特拉生坦血浆暴露的最强相关性。根据他们的 SLCO1B1 基因型，患者被分为正常（血浆浓度时间曲线下的阿曲生坦面积从零到无穷大（AUC_0−inf ) 41.3 ng·h/mL) 或慢速 (atrasentan AUC _0−inf 49.7 ng·h/mL, P  < 0.001) OATP1B1 转运蛋白表型。在具有正常 OATP1B1 表型的患者中，阿曲生坦对原发性肾脏和 HHF 结果的风险比 (HR) 为 0.61（95% 置信区间 (CI)：0.45–0.81）和 1.35（95% CI：0.84–2.13），分别。在慢转运蛋白表型中，肾脏和 HHF 结果的 HR 为 1.95（95% CI：0.95-4.03，P-相互作用正常表型 = 0.004）和 4.18（95% CI：1.37-12.7，P-相互作用正常表型 = 0.060 ）， 分别。OATP1B1 基因多态性与阿曲生坦血浆暴露以及长期疗效和安全性的显着患者间差异相关。