Kidney Week

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

• Diabetic Kidney Disease: Clinical - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Smeijer, Johannes David, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Johannes David Smeijer,

• Koomen, Jeroen, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Jeroen Koomen,

• Kohan, Donald E., University of Utah Health, Salt Lake City, Utah, United States

Donald E. Kohan,

• McMurray, John, University of Glasgow, Glasgow, Glasgow, United Kingdom

John McMurray,

• Bakris, George L., University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States

George L. Bakris,

• Correa-Rotter, Ricardo, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico

Ricardo Correa-Rotter,

• Hou, Fan Fan, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China

Fan Fan Hou,

• Kitzman, Dalane, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States

Dalane Kitzman,

• Makino, Hirofumi, Okayama Daigaku, Okayama, Okayama, Japan

Hirofumi Makino,

• Perkovic, Vlado, The George Institute for Global Health, Newtown, New South Wales, Australia

Vlado Perkovic,

• Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Capital Region, Denmark

Peter Rossing,

• de Zeeuw, Dick, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Dick de Zeeuw,

• L Heerspink, Hiddo Jan, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Hiddo Jan L Heerspink,

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 AUC_0-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.