Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Shanghai, China.
Clin Ther. 2021 Apr;43(4):735.e1-735.e14. doi: 10.1016/j.clinthera.2021.01.025. Epub 2021 Feb 27.
To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.
This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.
SPH3127 exposure, expressed as C, AUC, and AUC, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the C values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the C values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the C values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median T range from 0.33 to 1.0 h and the median t from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.
SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS.
NCT03128138 (SAD study) and NCT03255993 (MAD study).
评估健康个体中单剂量和多剂量 SPH3127 的药代动力学、药效学、安全性和耐受性。
这是一项随机、双盲、安慰剂对照的 I 期剂量递增研究。
SPH3127 的暴露量，以 C、AUC 和 AUC 表示，在 25-800mg（单递增剂量[SAD]）和 100-400mg 每日（多递增剂量[MADs]）范围内与剂量成比例增加。在 SAD 中，25、50、100、200、400 和 800mg SPH3127 的 C 值分别为 90.67、344.50、523.50、1239.50、2445.00 和 5753.33ng/mL。相应的 AUC 值分别为 294.48、843.62、1109.33、2858.56、6697.50 和 13057.83h×ng/mL。在 MADs 中，在 SPH3127 的第一剂后，100、200 和 400mg 的 C 值分别为 421.50、969.00 和 2468.33ng/mL。相应的 AUC 值分别为 1279.28、2275.77 和 5934.26h×ng/mL。在稳态时，100、200 和 400mg SPH3127 的 C 值分别为 514.67、1419.17 和 2513.33ng/mL。相应的 AUC 值分别为 1638.14、3096.20 和 7577.70h×ng/mL。T 中位数为 0.33-1.0h，t 中位数为 3-4h。在 SAD 中，当剂量>100mg 时，高达 90%的血浆肾素活性抑制持续长达 24h。在 MADs 中，最后一次给药后，每组的肾素活性持续抑制高达 90%，持续 24h。接受 SAD 的 29.2%和接受 MADs 的 33.3%的个体报告了治疗出现的不良事件（AE）。仅发生轻微的不良事件。
SPH3127 具有良好的耐受性，能够强有力且持续地抑制血浆肾素活性。
临床试验.gov 标识符：NCT03128138（SAD 研究）和 NCT03255993（MAD 研究）。
