Individual Atrasentan Exposure is Associated With Long‐term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease

Abstract

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.Endothelin receptor antagonists (ERAs) are a promising new treatment option for the prevention of end-stage kidney disease in patients with type 2 diabetes and chronic kidney disease (CKD).Experimental and clinical studies have shown that ERAs have favorable effects on risk markers of progression of CKD, such as albuminuria and systolic blood pressure, in addition to direct

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

“…We do not know why the higher exposure does not translate into increased kidney protection among slow transporters. A previous post hoc analysis from SONAR reported that a higher atrasentan exposure was, on average, associated with a more pronounced reduction in the risks of kidney outcomes 4 . However, we now show that in some patients with a higher exposure, atrasentan is not associated with increased kidney protection.…”

“…A previous post hoc analysis from SONAR reported that a higher atrasentan exposure was, on average, associated with a more pronounced reduction in the risks of kidney outcomes. 4 However, we now show that in some patients with a higher exposure, atrasentan is not associated with increased kidney protection. Because of the bidirectional relationship between heart failure and kidney failure it is possible that increased sodium retention during high exposure to atrasentan leads to edema and heart failure which may in turn accelerate kidney function decline.…”

“…Previous studies showed a considerable variability between patients in the response to atrasentan which was, at least in part, explained by a similar variability in drug exposure 3 . This between‐patient response variability to atrasentan determines the individual balance between benefits and risks of atrasentan 4 . Genetic polymorphisms may underly and contribute to the variability in atrasentan response.…”

“… 3 This between‐patient response variability to atrasentan determines the individual balance between benefits and risks of atrasentan. 4 Genetic polymorphisms may underly and contribute to the variability in atrasentan response. A better understanding of the genetic contribution to the between‐patient variability in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of atrasentan could aid in individualized therapy decisions.…”

Novel strategies in nephrology: what to expect from the future?

“…Bosentan and atrasentan are older ERA drugs that displayed some kidney protective actions in patients with CKD [ 137–139 ]. However, the pivotal phase 3 trial of atrasentan for diabetic kidney disease was terminated and despite kidney protection, it did not offer the cardiovascular protection associated to SGLT2 inhibition even though patients were carefully selected to minimize the adverse impact of sodium retention [ 139 , 140 ]. Sparsentan is both an endothelin receptor-A inhibitor and an angiotensin receptor blocker and was superior to irbesartan in reducing proteinuria in patients with focal segmental glomerular sclerosis, without any significant adverse effect [ 141 ].…”