Hedaya Mohsen A, Helmy Sally A
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Biopharm Drug Dispos. 2015 May;36(4):216-31. doi: 10.1002/bdd.1935. Epub 2015 Feb 4.
To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects.
A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared.
The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. Irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 .
A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610)
研究厄贝沙坦（IRB）与氢氯噻嗪（HCT）在血压正常受试者中的药代动力学/药效学（PK/PD）相互作用。
采用三交叉研究。在单独及联合给予厄贝沙坦和氢氯噻嗪后，监测系列药物浓度及药物效应，包括收缩压、舒张压和心率。将数据拟合至PK/PD模型，并比较单独及联合给药时厄贝沙坦和氢氯噻嗪的参数。
单剂量给药后，厄贝沙坦和氢氯噻嗪的血浆浓度曲线符合二室模型。氢氯噻嗪不影响厄贝沙坦的药代动力学参数；然而，厄贝沙坦使氢氯噻嗪的曲线下面积（AUC）降低25%，清除率增加25%。单独或联合给予每种药物后，心率均无显著变化。尽管厄贝沙坦的药代动力学未改变，但厄贝沙坦联合氢氯噻嗪比单独使用厄贝沙坦具有更强的降压作用。按时间顺序绘制的厄贝沙坦血浆浓度与其效应之间的关系呈逆时针滞后现象。与单独给予厄贝沙坦时相比，联合给予氢氯噻嗪时，厄贝沙坦对收缩压效应的药效学参数估计值有显著差异。表现为最大效应（Emax）增加25%，半数有效浓度（EC50）降低40%，提示联合用药具有协同降压作用。虽然氢氯噻嗪改变了厄贝沙坦对舒张压效应的参数估计值，但仅EC50的差异具有统计学意义。
在给定剂量下，观察到厄贝沙坦与氢氯噻嗪之间临床显著相互作用的可能性有限；因此，两种药物联合使用时均不建议调整剂量。（ClinicalTrials.gov标识符：NCT01858610）
