摘要
目的研究安纳拉唑钠肠溶片60,80或100 mg连续给药在健康受试者中的药代动力学、药效学和安全耐受性。方法采用随机、双盲双模拟、安慰剂和阳性药对照的试验设计,共计纳入45例中国健康受试者。各剂量组中10例受试者服用试验药物(安纳拉唑钠肠溶片60,80或100 mg),2例受试者服用阳性对照药(雷贝拉唑钠肠溶片20 mg),3例受试者服用安慰剂进行对照,每日1次给药,连续给药7 d。于首次给药前1天和给药第7天监测胃内24 h pH值。用液相色谱-串联质谱(LC-MS/MS)法定量检测血浆中安纳拉唑、安纳拉唑对映异构体及主活性代谢物(M21-1)的血药浓度。结果健康受试者口服安纳拉唑连续7 d后安纳拉唑原型药物已达稳态,平均达峰时间(Tmax)为4.3~4.8 h,平均消除半衰期(t1/2)分别为1.37~1.73 h,Cmax和AUC呈线性药代动力学特征,有轻度蓄积。稳态时安纳拉唑钠60,80或100 mg组安纳拉唑对映异构体的AUC与原型药物平均比例仅为4.93%~8.02%;主要活性代谢产物(M21-1)的AUC与原型药物平均比例为48.35%~55.86%。安纳拉唑钠60,80,100 mg组和雷贝拉唑20 mg、安慰剂组,给药前1天的24 h胃内pH值及24 h胃内pH值> 3、4、5的累积时间所占百分比[TpH≥3.0(%)、TpH≥4.0(%)和TpH≥5.0(%)]基本相近。给药后第7天(稳态)TpH≥3.0分别为79.85%,91.17%,81.29%,83.12%和40.40%;TpH≥4.0(%)分别为76.01%,87.63%,75.40%,77.84%和31.42%;TpH≥5.0(%)分别为68.97%,81.37%,68.73%,70.82%和23.63%。安纳拉唑钠肠溶片60 mg qd、80 mg qd和100 mg qd连续给药安全性和耐受性良好。未见与研究药物相关的严重不良事件。结论安纳拉唑钠肠溶片60 mg qd、80 mg qd和100 mg qd连续给药的安全性和耐受性良好,连续给药7天已达到稳态,有轻度蓄积。安纳拉唑钠肠溶片60 mg qd组、80 mg qd组和100 mg qd组均能持续抑制胃酸。
Objective To evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of anaprazole, a novel proton pump inhibitor after multiple-dose administration.Methods A double-blind, randomized, placebo and positive-controlled, dose-rising study was conducted in 45 healthy volunteers.The volunteers were randomly allocated to multiple-dose groups of 60 mg, 80 mg, 100 mg(15 subjects in each dose group including 10 subjects of anaprazole, 3 subjects of placebo and 2 subjects of rabeprazole 20 mg) once-daily for 7 consecutive days.Serial blood samples were collected and plasma concentrations of anaprazole and its enantiomer and its main metabolite(M21-1) for each dose group were determined by validated LC-MS/MS.Pharmacodynamic changes were measured by ambulatory intragastric p H monitoring.Results Plasma concentration of anaprazole reached the peak at 4.3-4.8 hours after administration with a terminal half-life(t1/2) of 1.37 to 1.73 hours in all the dosage groups.The pharmacokinetic characteristics of anaprazole showed linear with mild accumulation after multiple-dose administrations.The average ratio of enantiomer AUC/prototype AUC and main metabolite(M21-1) AUC/prototype AUC were of 4.93 to 8.02% and 48.35 to 55.86%.The mean 24-h p H values and the percentage of time at p H > 3,p H > 4,p H > 5 within 24 h were similar at baseline.At 7 thday,in anaprazole 60 mg,80 mg,100 mg,rabeprazole 20 mg and placebo group,the percentage of time at p H > 3 within 24 h were 79.85%,91.17%,81.29%,83.12% and 40.40%,the percentage of time at p H> 4 within 24 h were 76.01%,87.63%,75.40%,77.84% and 31.42%,the percentage of time at p H > 5 within24 h were 68.97%,81.37%,68.73%,70.82% and 23.63%.Multiple-doses administration of 60 mg,80 mg,100 mg anaprazole were safe and tolerable.No drug related serious adverse events were observed.Conclusion Multiple-dose administration of anaprazole were safe and well tolerated in healthy Chinese subjects.There was moderate accumulation after multiple doses administrations of anaprazole once daily for 7 consecutive days.Multiple-dose administration of 60 mg,80 mg,100 mg anaprazole provided significant and sustainable intragastric acid control.
作者
梁蓓蓓
王瑾
贾雨婷
王毅韬
陈莹
王睿
LIANG Bei-bei;WANG Jin;JIA Yu-ting;WANG Yi-tao;CHEN Ying;WANG Rui(Clinical Medicine Research Center,Chinese People's Liberation Army General Hospital,Beijing 100853,China;Xuanzhu Biopharmaceutical Lid,Bejing 100025,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2021年第4期447-453,共7页
The Chinese Journal of Clinical Pharmacology
关键词
安纳拉唑钠
药代动力学
药效学
耐受性
anaprazole
pharmacokinetics
pharmacodynamics
tolerability
