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目的评价高脂饮食对口服阿雷地平肠溶胶囊后健康中国人体内阿雷地平(AR)及其活性代谢产物羟基阿雷地平(AR-M1)的药动学(PK)、药效学(PD)的影响,并评价高脂饮食对该制剂的安全性的影响。方法采用随机、开放、自身交叉试验设计,12名健康受试者(男女各半)分两个阶段分别进行空腹和高脂餐后单次口服AR肠溶胶囊10 mg的PK试验,两次给药间隔7 d。每次给药前及给药后36 h内采集PK血样,采用液相色谱-串联质谱联用法(LC-MS/MS)测定健康受试者给药后血浆中AR及AR-M1的浓度。采用DAS2.1.1软件计算AR和AR-M1的主要PK参数(AUC0-t、AUC0-∞、mρax、tm ax、t1/2、Ke、CL/F、Vd/F等)。给药前及给药后36 h内分别测量收缩压(SBP)、舒张压(DBP)及心率作为药效学指标。整个试验过程中进行全面安全性评估。结果空腹和高脂餐后单次口服AR肠溶胶囊10 mg后,AR的AUC0-t、AUC0-∞、和tm ax有显著性差异(P<0.05)。AR-M1的tm ax有极显著性差异(P<0.01)。其他参数无显著性差异(P>0.05)。空腹和高脂餐后单次口服AR,受试者DBP、SBP发生不同程度降低,其中在给药后8 h两组受试者DBP均显著低于基线值(P<0.05),部分受试者心率加快,但无统计学差异;空腹及高脂餐后两组比较,受试者DBP、SBP及心率均无显著性差异。在空腹和高脂餐后给药,男女受试者的主要药动学参数及各药效学指标均无显著性别差异(P>0.05)。结论高脂饮食导致AR的吸收出现延迟现象,吸收程度显著增加;AR-M1的体内生成延迟;血压、心率无显著变化;本研究制剂安全性较好,试验过程无严重不良事件发生。综合考虑,临床应用不需调整用法用量,但应充分考虑病人的饮食习惯,建议空腹给药及清淡饮食。
Objective To evaluate the pharmacokinetics (PK) and pharmacodynamics (PK) of high-fat diet on the content of Areradipine (AR) and its active metabolite hydroxy-Areradipine (AR-M1) PD) and evaluate the effect of a high-fat diet on the safety of the formulation. Methods A randomized, open and self-crossover design was designed. Twelve healthy subjects (half male and half female) were divided into two groups and were given PK test of 10 mg single oral administration of AR enteric-coated capsules after fasting and high-fat meals respectively. Medicine interval 7 d. PK blood samples were collected before administration and within 36 hours after administration, and plasma concentrations of AR and AR-M1 in healthy subjects were determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The major PK parameters (AUC0-t, AUC0-∞, mρax, tm ax, t1 / 2, Ke, CL / F, Vd / F etc.) of AR and AR-M1 were calculated using DAS2.1.1 software. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured before treatment and within 36 h after administration as pharmacodynamic parameters. Conduct a comprehensive safety assessment throughout the trial. Results AUC0-t, AUC0-∞, and tm ax of AR after single oral administration of 10 mg of AR enteric-coated capsules after fasting and high-fat meals were significantly different (P <0.05). The tm ax of AR-M1 was significantly different (P <0.01). Other parameters no significant difference (P> 0.05). After a single oral dose of fasting and high-fat meal, DBP and SBP decreased to different extents. DBP of both groups were significantly lower than baseline at 8 h (P <0.05) The heart rate accelerated, but no statistical difference; fasting and high-fat meal after the two groups, subjects DBP, SBP and heart rate no significant difference. After fasting and high-fat meal administration, the main pharmacokinetic parameters and pharmacodynamic parameters of male and female subjects had no significant gender difference (P> 0.05). Conclusions The high-fat diet resulted in delayed absorption of AR and a significant increase of absorption. The in vivo production of AR-M1 was delayed. There was no significant change of blood pressure and heart rate. The preparation was safe and no serious adverse events occurred during the test. Taken together, clinical applications do not need to adjust the amount of usage, but should give full consideration to the patient’s diet, it is recommended fasting and light diet.