Abstract：
OBJECTIVE: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.
METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing.
RESULTS: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-h aldosterone suppression after 8 days of treatment, unlike the 8- and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge).
CONCLUSIONS: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.
METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing.
RESULTS: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-h aldosterone suppression after 8 days of treatment, unlike the 8- and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge).
CONCLUSIONS: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.
摘要：
目的：高醛固酮是高血压和长期阴性后遗症的关键驱动因素。我们评估了磷酸右法德罗坦（DP13）的安全性和有效性，一种新型醛固酮合成酶（CYP11B2）抑制剂，健康的参与者
方法：这是随机的，双盲,安慰剂对照研究分两部分进行.在A部分,单次递增剂量递增，16名参与者口服DP131-16mg。B部分是多次递增剂量，序贯小组研究，其中32名参与者口服DP134mg，8毫克或16毫克，每日一次，持续8天。在整个过程中监测安全性和耐受性。在最大血液药物浓度下的促肾上腺皮质激素（ACTH）刺激测试定义了多次给药的剂量范围。
结果：DP13在所有剂量下都具有良好的耐受性，无严重不良事件。在B部分,所有DP13剂量（4毫克，8毫克，16毫克）超过8天有效抑制醛固酮的产生，尿钠/钾比例增加，与安慰剂相比，血浆钠水平降低，血浆钾和肾素水平升高，导致醛固酮与肾素比率（ARR）的有效抑制。内分泌反调节导致4mg剂量在治疗8天后不再维持24小时醛固酮抑制，不同于8毫克和16毫克的剂量。没有证据表明药物诱导的肾上腺功能不全（ACTH应激激发）。
结论：在醛固酮过量和随后的钠潴留驱动高血压的患者中，管理钠平衡至关重要。CYP11B2抑制剂，如DP13，其有效性可以通过降低ARR来监测，可能被证明对治疗醛固酮依赖性高血压和原发性醛固酮增多症很有价值。
方法：这是随机的，双盲,安慰剂对照研究分两部分进行.在A部分,单次递增剂量递增，16名参与者口服DP131-16mg。B部分是多次递增剂量，序贯小组研究，其中32名参与者口服DP134mg，8毫克或16毫克，每日一次，持续8天。在整个过程中监测安全性和耐受性。在最大血液药物浓度下的促肾上腺皮质激素（ACTH）刺激测试定义了多次给药的剂量范围。
结果：DP13在所有剂量下都具有良好的耐受性，无严重不良事件。在B部分,所有DP13剂量（4毫克，8毫克，16毫克）超过8天有效抑制醛固酮的产生，尿钠/钾比例增加，与安慰剂相比，血浆钠水平降低，血浆钾和肾素水平升高，导致醛固酮与肾素比率（ARR）的有效抑制。内分泌反调节导致4mg剂量在治疗8天后不再维持24小时醛固酮抑制，不同于8毫克和16毫克的剂量。没有证据表明药物诱导的肾上腺功能不全（ACTH应激激发）。
结论：在醛固酮过量和随后的钠潴留驱动高血压的患者中，管理钠平衡至关重要。CYP11B2抑制剂，如DP13，其有效性可以通过降低ARR来监测，可能被证明对治疗醛固酮依赖性高血压和原发性醛固酮增多症很有价值。
