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

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 sub-study of the SONAR trial which enrolled adults with type 2 diabetes and chronic kidney disease [estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g]. Single nucleotide polymorphisms (SNPs) were determined for pre-specified membrane transporters, metabolizing enzymes and the endothelin-1 peptide. The associations between genotype, atrasentan plasma exposure and the effect of atrasentan on the pre-specified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3668 patients randomized, 2329 (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 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 with atrasentan for the primary kidney and HHF outcomes were 0.61 (95%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.