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Studied Zibotentan Doses Most commonly used dose * 5 mg orally once daily Dose range evaluated * 110 mg once daily * Doses above 5 mg increase edema risk without clear added benefit Dose Rationale * Zibotentan is highly selective for ETA, allowing effective pulmonary and vascular effects at lower doses * Nearmaximal ETA receptor occupancy occurs at 5 mg Clinical Implications * Designed to benefit PAH and mixed pre/postcapillary pulmonary hypertension * Potentially better tolerated in HFpEF phenotypes Zibotentan works by selectively blocking ETA receptors, reducing endothelin1mediated vasoconstriction and fibrosis while preserving ETBdependent nitric oxide release and natriuresis

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