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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.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2022 Nov; Vol. 112 (5), pp. 1098-1107. Date of Electronic Publication: 2022 Aug 11. - Publication Year :
- 2022
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Abstract
- 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 <superscript>2</superscript> , 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 <subscript>0-inf</subscript> ) 41.3 ng·h/mL) or slow (atrasentan AUC <subscript>0-inf</subscript> 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.<br /> (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Humans
Atrasentan adverse effects
Creatinine
Endothelin-1
Endothelin Receptor Antagonists
Albumins
Liver-Specific Organic Anion Transporter 1 genetics
Diabetic Nephropathies drug therapy
Diabetic Nephropathies genetics
Diabetic Nephropathies complications
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 genetics
Organic Anion Transporters genetics
Heart Failure chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 112
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 35892316
- Full Text :
- https://doi.org/10.1002/cpt.2721