Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Clin Ther. 2013 Jun;35(6):846-61. doi: 10.1016/j.clinthera.2013.04.014.
Co-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative.
This study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT.
This study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms.
Forty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone.
Both VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.
缬沙坦（VAL）和氢氯噻嗪（HCT）联合用药可用于调节血压。一些患者可能难以遵守多药物治疗方案；因此，VAL+HCT 联合片剂可能是一种合适的替代方案。
本研究旨在比较健康埃及受试者空腹时口服固定剂量复方（FDC）片剂和同时服用两种药物时 VAL 和 HCT 的吸收速率和程度。该研究还扩展到研究 VAL 和 HCT 之间是否存在任何潜在相互作用。
该研究采用开放标签、随机研究，分为两部分（第 I 部分和第 II 部分），每部分包括 4 个单剂量治疗期和 2 周洗脱期的交叉设计。在给药后 48 小时内采集血样，并通过 HPLC 分析血浆中 VAL 和 HCT 的浓度。比较 VAL 和 HCT 联合给药后每种药物的药代动力学特性与单独给药后每种药物的药代动力学特性。通过体检和询问受试者的舒适度和不适感觉来评估耐受性。所有受试者报告的事件均记录在不良事件表格中。
共纳入 48 名健康受试者（每部分 24 名），所有受试者均完成了研究。在研究期间或完成后，没有参与者出现任何药物不良反应的迹象。统计分析证实，VAL/HCT FDC 和 VAL+HCT 的 AUC 和 Cmax 的 90%CI 在 0.8 到 1.25 之间的普遍接受的生物等效性范围内。因此，从体内药代动力学的角度来看，1 片 FDC 片剂可以被认为在医学实践中与 2 种个体参考片剂可互换。然而，VAL 单独给药和与 HCT 联合给药（无论是作为 FDC 还是同时给药）之间的 90%CI 表明 VAL 和 HCT 之间存在相互作用，这会显著降低 VAL 吸收的系统暴露和强度。与单独给予 HCT 相比，HCT 与 VAL 联合给药对 HCT 的 AUC 和 Cmax 的影响不显著。
VAL/HCT FDC 和 VAL+HCT 均具有良好的耐受性。VAL+HCT 联合治疗的安全性/疗效可扩展到 VAL/HCT FDC 片剂。应研究 HCT 与其他血管紧张素受体阻滞剂之间的相互作用，以确定这种相互作用是否仅限于 VAL，或者其他血管紧张素受体阻滞剂是否具有相同的药代动力学相互作用。需要进一步研究以确定外排和摄取转运体对 VAL 和 HCT 处置和药代动力学的作用。
