安纳拉唑钠肠溶片在健康受试者中多次给药的药代动力学、药效学和耐受性研究

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...

Tolerance,pharmacokinetics, and pharmacodynamics of anaprazole in multiple-dose administration in healthy Chinese subjects

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.