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) be- tween olmesartan medoxomil and hydrochlo- rothiazide (HCTZ), to confirm bioequivalence (BE) of a new combined formulation and co- administration 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 fol- lowing regimens in a sequence as Latin square (4 × 4) design: A: olmesartan medoxomil; B: HCTZ; C: test drug (new combined formula- tion); D: reference drugs (co-administration of separate tablets). In stage 2, half of 28 sub- jects 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 signifi- cant 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 sig- nificant accumulation was observed. The new combination formulation is reasonably toler- ated well in healthy Chinese subjects after multiple doses.