餐时给药条件下盐酸伊伐布雷定片在健康人体的药动-药效学研究

Evaluation of pharmacokinetics and pharmacodynamics after administration during meals of ivabradine hydrochloride in healthy volunteers

目的:阐明健康志愿受试者经单次和多次餐时口服盐酸伊伐布雷定片后,原型药伊伐布雷定、代谢产物去甲伊伐布雷定(S-18982)的体内动态变化规律及其对心率和心率-收缩压乘积的影响。方法:(1)采用随机、开放、自身交叉设计的研究方法。12名受试者交叉单次餐时口服盐酸伊伐布雷定片5、10和15 mg,采集给药前及给药后0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12、24、36和48 h血样。单次给药结束后12名受试者分别于早、晚餐时用药各5 mg,连续5 d(共9次),采集第3~5天早上用药前、第5天早上用药后(按单次给药时间点)血样。用LC-MS/MS法测定伊伐布雷定和S-18982血药浓度,DAS 3.0计算药代参数并评价药物蓄积性。(2)采集单次给药各周期和多次给药第5天给药前及给药后24 h内心率和血压,进行药效分析。结果:(1)单次给药5、10和15 mg后,原型药及S-18982的C_(max)分别为(18±7)、(36±18)和(45±24)μg/L,(2.6±0.8)、(4.9±1.9)和(6.9±1.7)μg/L;AUC0-48 h分别为(55±20)、(124±47)和(186±79)μg·h·L^(-1),(15±4)、(35±9)和(57±15)μg·h·L^(-1)。原型药和S-18982的t_(max)、t1/2分别在1.5~1.9 h、2.3~2.9 h和1.8~2.4 h、8.0~9.3 h范围内。多次给药5 mg后原型药和S-18982的C_(max)、AUC_(0-48 h)分别为(21±9)、(78±31)μg/L和(3.6±1.3)、(34±14)μg·h·L^(-1)。(2)药物对受试者心率和心率-收缩压乘积都有降低作用且呈剂量依赖性,给药后约3 h(比t_(max)延迟约1~2 h)时作用最强,可持续至9~12 h。结论:(1)餐时给药条件下单次给药伊伐布雷定及其代谢产物S-18982的吸收程度C_(max)和AUC_(0-48 h)在5~15 mg剂量范围内呈线性规律;原型药吸收达峰较S-18982略快,消除较S-18982快。多次给药后两物质血浆浓度与单次给药相比有所提高,但均无明显蓄积情况发生。(2)盐酸伊伐布雷定片可降低健康受试者心率、心率-收缩压乘积,对收缩压影响较小。

AIM： To explore pharmacokinetic and pharmacodynamics characteristics after administration during meals of ivabradine hydrochloride in healthy Chinese volunteers. METHODS ： （ 1 ） This was a randomized, open-label, self crossover, single- and multiple-dose study conducted in healthy subjects. 12 subjects received a single oral dose of ivabradine 5, 10, and 15 mg. Blood samples were collected predose and at 0.25,0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, and 48 hours after administration during meals each period. After a single dose, the subjects received repeated oral doses of 5 mg ivabradine BID for 5 days （ a total of 9 times）. The predose blood samples were collected on days 3 and 4. On the last day, blood samples were drawn at the identical time as in the single-dose study. The plasma concentrations of ivabradine and its metabolite S-18982 were determined by using validated LC-MS/MS, and the PK parameters were calculated by DAS 3.0. （2） For PD measurements, heart rate and blood pressure were taken at each of the following times： Before and after single-dose during each period and the last day of multipledose. RESULTS： （1） After single dose of 5, 10 and 15 mg, the Cmax of ivabradine were （18 ±7）, （36 ±18） and （45 ±24） txg/L; the AUC0-48hof ivabradine were （55 ±20）, （124 ±47） and （186 ±79） μg·h·L^-1 ; the Cmax of S-18982 were （2.6 ±0.8）, （4.9±1.9） and （6.9 ±1.7） μg/L; the AUCo.48hof S-18982 were （15 ±4）, （35 ±9） and （57 ± 15）μg·h·L^-1, respectively. The tmax and t1/2 of ivabradine in the ranges of 1.5 to 1.9 hours＇ and 2.3 to 2.9 hours： The t and t1/2 of S-18982 in the ranges of 1.8 to 2.4 hours＇and 8.0 to 9.3 hours＇. After multiple doses of 5 mg, the Cmax and AUC0-48hof ivabradine were （21 ±9） μg/L and （78 ±31） μg·h·L^-1; the Cmax and AUC0-48hof S- 18982 were （3.6 ±1.3） μg./L and （34±14） μg·h·L^-1, respectively. （ 2 ） Ivabradine hydro- chloride observed a heart rate and rate pressure product reduction effects and all generally showed a dose-dependent tendency. The maximum effects achieved at 3 hours （which was about 1 to 2 hours later than tmax） after administration, and lasting 9 to 12 hours. CONCLUSION ： （ 1 ） Cm,x and AUCo.4s h values for both ivabradine and S-18982 increased linearly with ivabradine hydrochloride dose after single dose over the range of 5 to 15 mg. The absorption peak time of ivabradine was slightly faster than that of S-18982, and the elimination rate was faster than that of S-18982. The plasma concentrations of the two substances were improved after multiple dosing, but no obvious accumulation occurred. （2） Ivabradine hydrochlorid tablets can reduce heart rate and rate pressure product in healthy subjects, but less effects on diastolic blood pressure.