Zydus Research Center, Survey No. 396/403, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat, 382213, India.
Division of Nucleus Network, Centre for Clinical Studies (CCS), Melbourne, Australia.
Clin Pharmacokinet. 2018 Jan;57(1):87-102. doi: 10.1007/s40262-017-0551-3.
This phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers.
The study was a randomized, double-blind, placebo-controlled phase I study carried out in two parts in addition to a third part involving an open-label study to evaluate the food/sex effect. A total of 100 subjects were enrolled into the study as follows: part I-single-dose study with ZYAN1 10, 25, 50, 100, 150, 200, and 300 mg (n = 56); part II-multiple-dose study with every other day dosing of ZYAN1 100, 150, 200, and 300 mg (n = 32); and part III-sex and food effect study with ZYAN1 150 mg (n = 12; open-label).
ZYAN1 was well-tolerated after single and multiple oral ascending doses. No drug-related serious adverse events were reported. Following a single ascending dose of ZYAN1, the maximum concentration (C ) ranged from 566.47 ± 163.03 to 17,858.33 ± 2899.19 ng/mL and the median time to C (t ) was approximately 2.5 h for the studied 30-fold oral doses of ZYAN1. Regardless of single or multiple doses, mean C and area under the concentration-time curve from time zero to time t (AUC ) values generally showed a dose-proportional increase. The mean elimination half-life (t ) of ZYAN1 ranged from 6.9 to 13 h with negligible accumulation. Following a single dose of ZYAN1, the mean serum erythropoietin (EPO) C values showed dose response (i.e., 6.6 and 79.9 mIU/L for 10 and 300 mg ZYAN1 doses, respectively), while the time to mean maximal serum EPO concentrations ranged from 10 to 72 h.
Oral single (10-300 mg) and multiple dosing (100-300 mg) of ZYAN1 in healthy subjects was found to be safe and well-tolerated. With increasing ZYAN1 dose, there was almost a proportional increase in mean C and AUC . The mean serum EPO concentrations showed a trend of dose response. Based on the t , pharmacodynamic activity, and lack of drug accumulation, a once every 2 days dosing regimen of ZYAN1 was appropriate for phase II study.
Australian New Zealand Clinical Trials Registry trial ID ACTRN12614001240639.
本 I 期研究旨在评估 ZYAN1 口服给药后在健康志愿者中的安全性、耐受性和药代动力学。
该研究是一项随机、双盲、安慰剂对照的 I 期研究，分为两部分进行，此外还进行了第三部分开放性研究，以评估食物/性别效应。共有 100 名受试者入组研究，具体如下：第一部分单剂量研究，ZYAN1 10、25、50、100、150、200 和 300mg（n=56）；第二部分多剂量研究，每隔一天给予 ZYAN1 100、150、200 和 300mg（n=32）；第三部分性别和食物效应研究，给予 ZYAN1 150mg（n=12；开放性）。
ZYAN1 在单次和多次递增口服剂量后耐受性良好。未报告与药物相关的严重不良事件。单次递增剂量 ZYAN1 后，最大浓度（C ）范围为 566.47±163.03 至 17858.33±2899.19ng/mL，研究的 30 倍口服剂量 ZYAN1 的中位 C （t ）约为 2.5h。无论单次或多次给药，平均 C 和从零时到 t 时间的浓度-时间曲线下面积（AUC ）值均表现出剂量比例增加。ZYAN1 的平均消除半衰期（t ）为 6.9 至 13h，几乎无蓄积。单次给予 ZYAN1 后，平均血清促红细胞生成素（EPO）C 值呈剂量反应（即 10 和 300mg ZYAN1 剂量分别为 6.6 和 79.9mIU/L），而平均最大血清 EPO 浓度时间范围为 10 至 72h。
在健康受试者中，口服单次（10-300mg）和多次（100-300mg）给予 ZYAN1 被发现是安全且耐受良好的。随着 ZYAN1 剂量的增加，平均 C 和 AUC 几乎呈比例增加。平均血清 EPO 浓度呈剂量反应趋势。基于 t 、药效学和无药物蓄积，ZYAN1 每 2 天一次的给药方案适合进行 II 期研究。
澳大利亚和新西兰临床试验注册处注册号 ACTRN12614001240639。
