Objective: To compare the pharmacokinetic (PK) profiles and evaluate the PK interaction of hydrochlorothiazide (HCTZ) used alone and in combination with benazepril (BENA) or valsartan (VAL) in healthy Chinese volunteers.
Materials and methods: Data from two Phase I clinical trials (Study A and Study B) were combined and analyzed. Study A was an open, randomized, three-period crossover study. Eligible healthy male Chinese volunteers were randomly assigned to receive a single dose of the HCTZ (25 mg), BENA (20 mg) or HCTZ/BENA (25/20 mg). Study B was an open randomized, two-period crossover study of VAL/HCTZ (160/12.5 mg) in two formulations. A 7-day washout period was designed between alternate formulations in both studies. Multiple blood samples were collected up to 48 h post-dose, and plasma concentrations of HCTZ were analyzed using high performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS) system. Adverse events (AEs) were monitored and documented throughout the study period.
Results: 12 subjects completed Study A and 18 subjects completed Study B. Mean maximum plasma concentration (C(max)) was 168, 121 and 418 ng/ml and mean exposure (AUC(0-48 h)) was 1,160, 955 and 2,801 ng × h/ml following a single dose of HCTZ (25 mg) alone, BENA/HCTZ (20/25 mg) and VAL/HCTZ (160/12.5 mg), respectively. There was significant decrease in C(max) (90% confidence interval: 64.4 - 78.0%) and AUC(0-48 h) (90% confidence interval: 75.9 - 89.5%) of HCTZ with BENA co-administration, whereas concomitant VAL with HCTZ led to significant increase (approximate 1.5-fold) in C(max) and AUC(0-48 h) of plasma HCTZ even without dose normalizing. The apparent terminal half-life (t(1/2)) and the time to C(max) (tmax) were unchanged between the two studies. Overall, HCTZ alone as well as in combination with BENA and VAL was well tolerated within the scope of the current studies in Chinese health volunteers.
Conclusions: BENA decreased the bioavailability of HCTZ in Chinese healthy volunteers while VAL greatly increased the concentration of HCTZ in plasma during coadministration. The combination of HCTZ with BENA or VAL was safe and well tolerated.