Pharmacokinetics and tolerability of olmesartan medoxomil plus hydrochlorothiazide combination in healthy Chinese subjects: drug-drug interaction, bioequivalence, and accumulation.

OBJECTIVES: The study is to investigate drug-drug interaction (DDI) between olmesartan medoxomil and hydrochlorothiazide (HCTZ), to confirm bioequivalence (BE) of a new combined formulation and coadministration of separate local tablets, and to receive pharmacokinetics and tolerability of the new combined formulation after multiple doses in healthy Chinese subjects. METHODS: The 3-in-1 study was separated into 2 stages. Stage 1 is a four-period crossover study. 28 healthy subjects were equally randomized into four groups. Each group received the four following regimens in a sequence as Latin square (4 × 4) design: A: olmesartan medoxomil; B: HCTZ; C: test drug (new combined formulation); D: reference drugs (co-administration of separate tablets). In stage 2, half of 28 subjects were daily dosed with regimen C for 7 days. Blood and urine samples were obtained to receive pharmacokinetics of olmesartan and HCTZ, which were analyzed using the BE evaluation method. Tolerability was also assessed. RESULTS: All subjects completed the study and nobody reported serious adverse event (SAE). The 90% confidence intervals (CI) of geometric mean ratio (GMR) of log transformed Cmax, AUC0-t, and AUC0-∞ after single dose showed no DDI and claimed BE. The mean ratio of accumulation (Ra) (SD) of olmesartan and HCTZ after multiple doses of new combination formulation is 1.03 (0.182) and 0.954 (0.128). CONCLUSIONS: No significant DDI between olmesartan and HCTZ was found. The new combination formulation is bioequivalent to co-administration of two separate local tablets. After multiple doses of the new combination formulation, no significant accumulation was observed. The new combination formulation is reasonably tolerated well in healthy Chinese subjects after multiple doses.

A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects.

AIM: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. METHODS: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 µg·kg(-1)·min(-1), each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. RESULTS: Peak concentrations (C(max)) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107-0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL(-1) (range, 3.2-6.8 ng·h·mL(-1)). The volume of distribution (V) was 48 L (range, 30.8-80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E(0), E(max), and EC(50) were 68 bpm, 73 bpm and 8.1 µg/L, respectively. CONCLUSION: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.