Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight

Abstract

This study aimed to identify the optimal dose of the endothelin‐1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR‐JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin‐to‐creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).

Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta‐analysis of randomized controlled trials

“…In this study, dose-response analysis indicated that 0.75 mg/ day atrasentan exerted a similarly significant benefit on albuminuria with less incidence of fluid retention vs a dose of ≥1.25 mg/day, suggesting that 0.75 mg/d atrasentan is optimal to provide renal protection with fewer safety concerns. This result is consistent with a previous post hoc analysis of the RADAR-JAPAN study, 36 which evaluated the exposureresponse relationships of albuminuria and body weight, and suggested that 0.75 mg/day atrasentan is the optimal dose for kidney protection with maximal efficacy and minimal fluid retention risks. Even so, it is still not possible to state that atrasentan does not increase the risk of CHF.…”

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

“…This high variability in response to atrasentan has been observed before in phase 2 studies 3,6 . In an earlier, comparatively small phase 2 trial, a greater albuminuria reduction was observed in Asian patients compared with North American patients, which was linked to higher atrasentan plasma concentrations in Asian patients 9,10 . In the current study, the albuminuria response was similar between Asian and Caucasian patients.…”

“…The relationship between plasma exposure and albuminuria indicates that additional albuminuria lowering can be achieved by increasing the plasma exposure using a higher dose of atrasentan. However, the maximum dose is limited by the fluid‐retention effects of atrasentan, and increasing the atrasentan plasma exposure will also result in more fluid retention 10 . This highlights the need for establishing a therapeutic window, during which fluid retention is kept at a minimum, while albuminuria lowering is optimized.…”

“…However, albuminuria‐lowering and fluid‐retention effects of atrasentan have been shown to vary considerably among patients even when patients receive the same dose of atrasentan 8 . Post hoc analyses of a phase 2 clinical trial in patients with T2D and CKD showed that part of this variability in kidney protection and fluid‐retention effects of atrasentan can be explained by the plasma concentration of atrasentan and patient characteristics 9,10 . However, the sample size of this study was small, which limited the robustness and precision of the results.…”

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

“…This range in plasma exposure corresponded to a balance between kidney protection and fluid retention, which favored kidney protection, and was therefore used as reference. 7 Association between plasma exposure and long-term outcomes Parametric time-to-event models were developed to investigate the association between atrasentan plasma exposure and both composite outcomes. For both outcomes, model development initiated by evaluation of several model structures that could adequately describe the hazard of developing an event over time in the placebo group.…”