Bioequivalence and comparison of pharmacokinetic properties of 4-mg tablet formulations of rosiglitazone hydrochloride and rosiglitazone maleate: A single-dose, randomized, open-label, two-period crossover study in healthy adult male Chinese volunteers

Abstract

Background: Rosiglitazone is an insulin-sensitizing oral thiazolidinedione used for treating patients with type 2 diabetes mellitus. There are 9 oral generic and branded formulations of rosiglitazone available in the People's Republic of China (PRC); however, a literature search did not identify any published data concerning the bioavailability of these formulations in the Chinese population. Objectives: The aims of this study were to compare the pharmacokinetic properties and determine the bioequivalence of 2 formulations of rosiglitazone 4-mg tablets—rosiglitazone hydrochloride (test) and rosiglitazone maleate (reference)—in healthy adult male Chinese volunteers. Methods: This single-dose, randomized, open-label, 2-period crossover study was conducted at Zhejiang Provincial People's Hospital, Hangzhou, PRC. Healthy adult male Chinese volunteers were randomly assigned to receive a single 4-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a ≥12-hour (overnight) fast. Plasma was analyzed for rosiglitazone concentration using a validated high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C max, AUC 0-t, and AUC 0-∞, blood samples were drawn before (0 hour; baseline) and at 10, 20, 30, 45, 60, 75, and 90 minutes and 2, 4, 6, 8, 12, and 24 hours after administration. The formulations were to be considered bioequivalent if the logarithm-normal (ln)-transformed ratios of C max and AUC were within the predetermined range of 80% to 125%, as established by the US Food and Drug Administration. Tolerability was assessed using physical examination, including monitoring of vital signs, laboratory testing (hematology, blood biochemistry, hepatic function, renal function, and urinalysis), and questioning subjects about adverse events (AEs). Results: Twenty subjects were enrolled and completed the study (mean [SD] age, 21.1 [1.4] years; weight, 62.6 [4.6] kg; height, 171 [5] cm; and body mass index, 21.4 [1.3] kg/m 2). No period or sequence effects were detected. The 90% CIs for the ln-transformed ratios of C max, AUC 0-24, and AUC 0-∞ were 96.79 to 109.73, 92.14 to 102.93, and 91.64 to 102.60, respectively (all, P < 0.001), meeting the predetermined criterion for bioequivalence. No AEs were reported in this study. Conclusions: In this small study in these healthy adult male Chinese volunteers, a single 4-mg dose of rosiglitazone hydrochloride appeared to be bioequivalent to rosiglitazone maleate, according to the regulatory definition, based on the rate and extent of absorption. Both formulations were well tolerated.