在健康的中国和白种人志愿者中，Tenapanor 的药代动力学、安全性和耐受性：一项随机、开放标签、单中心、安慰剂对照的 1 期研究。
Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.
机构信息
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Global R&D Center, Shanghai Fosun Pharmaceutical Development, Co., Ltd, Shanghai, China.
出版信息
Int J Clin Pract. 2024 Mar 6;2024:1386980. doi: 10.1155/2024/1386980. eCollection 2024.
BACKGROUND
Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects.
METHODS
This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio.
RESULTS
59 healthy volunteers received tenapanor 10 mg ( = 12 Chinese), 30 mg ( = 12 Chinese), or 50 mg ( = 12 (Chinese), = 11 (Caucasian)) or placebo ( = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean , AUC, and AUC of tenapanor-M1 increased with increasing dose level, and AUC increased approximately dose proportionally. The accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred.
CONCLUSION
Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.
背景
Tenapanor 是一种局部作用的选择性钠-氢交换体 3 抑制剂，具有治疗各种心肾疾病中钠/磷和液体超负荷的潜力，已在美国获批用于治疗以便秘为主的肠易激综合征。本研究旨在评估 tenapanor 及其代谢物 tenapanor-M1（AZ13792925）在健康中国和白种人群体中的药代动力学（PK）、安全性和耐受性。
方法
这是一项在中国和白种健康志愿者中进行的随机、开放标签、单中心、安慰剂对照的 I 期研究（https://www.chinadrugtrials.org.cn；CTR20201783）。该研究共招募了 4 个平行队列（3 个队列用于中国受试者，1 个队列用于白种受试者），每个队列预计纳入 15 名受试者，接受口服 tenapanor（10 或 30mg 单剂量，或 50mg 单剂量，随后第 5 至 11 天每天重复给药 2 次，第 11 天早上单次给药）或安慰剂，比例为 4:1。
结果
59 名健康志愿者接受了 tenapanor 10mg（ = 12 名中国受试者）、30mg（ = 12 名中国受试者）或 50mg（ = 12 名中国受试者、 = 11 名白种受试者）或安慰剂（ = 12 名，每个队列 3 名）。单次和每日重复给药后，tenapanor 血浆浓度均低于定量下限；tenapanor-M1 缓慢出现在血浆中。在 10 至 50mg 的单递增剂量评估中（在中国受试者中），tenapanor-M1 的平均 Cmax、AUC 和 AUC 随剂量水平增加而增加，AUC 约呈剂量比例增加。在接受 tenapanor 50mg 的中国和白种受试者中，重复给药后 50mg 的蓄积比为 1.55 至 6.92。tenapanor-M1 的暴露量在中白种受试者之间总体相似。tenapanor 总体耐受良好，接受 tenapanor 50mg 的中国和白种受试者的安全性特征相似，通过生命体征、体格检查、实验室检查、12 导联心电图和不良事件来评估。未发生严重不良事件或导致停药的不良事件。
结论
tenapanor 在中白种受试者中的耐受性良好，PK 和安全性特征相似。本试验在中国临床试验注册中心注册，注册号为 CTR20201783。
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