Organic Anion Transporter Gene Variants Associated With Plasma Exposure and Long‐Term Response to Atrasentan in Patients With Diabetic Kidney Disease

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 2 , 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 plasmaconcentration 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 betweenpatient variability in atrasentan plasma exposure and long-term efficacy and safety.

Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?

“…Even though alterantive allele protectiveness might be explained by longer drug exposure and similar results were present in several studies [46,47], those studies were focusing on different diseases and outcomes. Other study did not associate slow OATP1B1 transporters, or SLCO1B1 variant carriers, with reduced risk for kidney and heart failure in Diabetic Kidney Diseases patients [48]. Results of our study concerning SLCO1B1 rs4149056 are somewhat contradictory to previouse research focusing variant carriers as more prone to developing adverse drug reactions and less responsive to therapy [49,50].…”

Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease

“…These partially explained the variability in effect and point to the need to tailor dosing to individual patient characteristics to achieve optimal outcomes [ 39 ]. Another potential modifying factor is genetics, as OATP1B1 gene polymorphisms encoding a hepatic organic anion transporter, have been shown to affect between-patient variability in atrasentan plasma exposure and to be associated with long-term efficacy and safety [ 40 ]. A pharmacokinetic reanalysis quantifying the dose–response relationships with efficacy endpoints and safety events showed that atrasentan 0.75 mg/day provided a mean exposure that translated to a reduction of 24% in the hazard of kidney events and an increase of 13% in the hazard of heart failure, confirming the good risk–benefit profile [ 41 ].…”