Inter‐individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: A post hoc analysis of the SONAR trial

Abstract

Aim To evaluate whether atrasentan plasma exposure explains between‐patient variability in urinary albumin‐to‐creatinine ratio (UACR) response, a surrogate for kidney protection, and B‐type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run‐in period. Individual area under the concentration‐time‐curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th‐97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was −36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th‐97.5th P: −76.2% to 44.5%; BNP, 2.5th‐97.5th P: −71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion Atrasentan plasma exposure varied among individual patients and partially explained between‐patient variability in efficacy and safety response.

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

“…This plasma exposure can then be used to determine the individual benefit / risk balance but should ideally also take into account other relevant patient characteristics that determine the long-term risk on kidney and heart failure outcomes as well as likelihood to respond to atrasentan. 10 Dose selection, based on short-term changes in risk markers for kidney protection and fluid retention, translated in a favorable balance toward long-term kidney protection. In addition to plasma exposure, we found that other patient characteristics also influenced long-term treatment outcome.…”

“…On an individual level, an estimate of plasma exposure can be obtained using the population pharmacokinetic model using dosing information, sampling information, and plasma‐concentration. This plasma exposure can then be used to determine the individual benefit / risk balance but should ideally also take into account other relevant patient characteristics that determine the long‐term risk on kidney and heart failure outcomes as well as likelihood to respond to atrasentan 10 …”

“…Plasma samples were obtained throughout the double‐blind period of the trial at several study visits prior to dosing. We used a previously developed population pharmacokinetic model to estimate atrasentan plasma exposure in the double‐blind period of the trial 10 . In this model, the plasma concentration of atrasentan over time is described using patient characteristics, measured plasma concentrations, dose of atrasentan, and information about sampling and dosing times.…”

“…We used a previously developed population pharmacokinetic model to estimate atrasentan plasma exposure in the double-blind period of the trial. 10 In this model, the plasma concentration of atrasentan over time is described using patient characteristics, measured plasma concentrations, dose of atrasentan, and information about sampling and dosing times. Pharmacokinetic parameters of atrasentan, such as clearance and volume of distribution, are estimated for the entire population.…”

Endothelin receptors in renal interstitial cells do not contribute to the development of fibrosis during experimental kidney disease

“…These trials performed with various ETA antagonists show reno-protective effects by reducing proteinuria in patients with chronic kidney disease and type 2 diabetes [12,21,22,34,36,42,54,61] which shows us that the results from a selective, cell-specific deletion of the ET receptors in the animal model are hardly transferable to human kidney diseases.…”