Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Baxdrostat 是一种选择性醛固酮合酶抑制剂，设计用于治疗与醛固酮升高相关的疾病。本研究评估了在健康志愿者中多次递增剂量的 baxdrostat 的安全性、药代动力学和药效学。受试者被随机分配接受口服 baxdrostat（0.5、1.5、2.5 或 5.0 mg）或安慰剂，每天一次，持续 10 天，并在研究期间接受低盐或正常盐饮食。在第 1 天和第 10 天给药前后采集血样，以表征药代动力学和药效学。安全性通过不良事件、身体检查、心电图、直立性生命体征和临床实验室评估进行评估。54 名受试者完成了研究。没有死亡或严重不良事件，接受baxdrostat的受试者的所有治疗紧急不良事件的严重程度均为轻度。Baxdrostat 的血浆水平随剂量增加成比例增加，在给药后 4 小时内观察到峰值浓度，平均半衰期为 26 至 31 小时。无论饮食如何，baxdrostat 剂量≥1.5 mg 时血浆醛固酮剂量依赖性降低发生。血浆醛固酮持续降低，第 10 天水平降低约 51% 至 73%。Baxdrostat 对血浆皮质醇水平没有有意义的影响，导致血浆钠水平轻度剂量依赖性降低和钾水平升高。Baxdrostat 安全且耐受性良好，半衰期支持每日一次给药。