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Abstract: TH-PO244

Gene Polymorphism in Organic Anion Transporters Determine the Long-Term Efficacy and Safety of Atrasentan in Patients With Type 2 Diabetes and CKD

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Koomen, Jeroen, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kohan, Donald E., University of Utah Health, Salt Lake City, Utah, United States
  • McMurray, John, University of Glasgow, Glasgow, Glasgow, United Kingdom
  • Bakris, George L., University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
  • Correa-Rotter, Ricardo, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • Hou, Fan Fan, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  • Kitzman, Dalane, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • Makino, Hirofumi, Okayama Daigaku, Okayama, Okayama, Japan
  • Perkovic, Vlado, The George Institute for Global Health, Newtown, New South Wales, Australia
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region, Denmark
  • de Zeeuw, Dick, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • L Heerspink, Hiddo Jan, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
Background

The 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.

Methods

We performed a genetic sub-study of the SONAR trial in adults with type 2 diabetes, and estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g. Single nucleotide polymorphisms (SNPs) were determined in pre-specified membrane transporters, metabolizing enzymes and the endothelin-1 peptide, based on expected relevance for atrasentan PK/PD. 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.

Results

Of 3668 randomized patients, 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- or slow OATP1B1 transporter phenotypes. The slow OATP1B1 transporter phenotype group (15.9% of total cohort) had a 20.3% higher atrasentan AUC0-inf compared to the normal phenotype (geometric mean AUC 49.7 versus 41.3 ng.h/mL; p<0.001). Among patients with a normal OATP1B1 transporter 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 contrast, 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.

Conclusion

Genetic polymorphisms in OATP transporters are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.