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In the PROTECT study, sparsentan, which targets both the endothelin type A (ETAR) and angiotensin type 1 (AT1R) receptors, reduced proteinuria vs active comparator in immunoglobulin A nephropathy (IgAN), with minimal changes in fluid status. This contrasts with greater fluid retention, including heart failure hospitalization, in studies using agents targeting ETAR alone. This may relate to differences in comorbidities; however, aspects of dual receptor binding by sparsentan may also be a factor. Since ETAR blockers favor fluid retention while AT1R blockers may promote fluid excretion, continual high blockade of AT1R during ETAR blockade may help maintain normal fluid balance. The pharmacokinetic (PK) properties of sparsentan were used to estimate diurnal changes in receptor occupancy (RO) at steady state in the PROTECT study.
Receptor affinities (inhibitory constant [Ki]) were determined for sparsentan at ETAR, ETBR, and AT1R using radioligand binding assays. Population PK modeling of sparsentan was used to derive 24-hour PK and RO profiles of patients in PROTECT.
Sparsentan receptor affinities and PK data of a typical patient with IgAN in PROTECT are shown in the Figure. The 24-hour plot of sparsentan RO for ETAR, ETBR, and AT1R using PK data estimated for 400 mg daily shows RO is >60% and <90% for ETAR, >95% for AT1R, and <2% for ETBR.
Sparsentan has a stable 24-hour relationship in relative RO of ETAR to AT1R, in which AT1R occupancy always exceeds ETAR occupancy. In contrast, when a drug solely targets ETAR, on top of AT1R blockade, periods of relatively unaccompanied ETAR antagonism may occur, representing a risk for fluid retention. This could partly explain the fluid retention seen with endothelin receptor antagonists and the minimal changes in fluid status seen with sparsentan.
Figure. Sparsentan Steady-State PK (Left Axis) and Receptor Occupancies (Right Axis) Over 24 Hours Following a Single Daily 400 mg Oral Dose in PROTECT*