Relative bioavailability of generic and branded acetylcysteine effervescent tablets: A single-dose, open-label, randomized-sequence, two-period crossover study in fasting healthy chinese male volunteers

Abstract

Background: Acetylcysteine may be used as a muco- lytic agent for the treatment of chronic bronchitis, chronic obstructive pulmonary disease, and other pul- monary diseases complicated by the production of viscous mucus. However, little is known of its pharma- cokinetic properties when given orally in healthy vol- unteers, particularly in a Chinese Han population. This study was conducted to provide support for the market- ing of a generic product in China. Objective: The purpose of this study was to compare the pharmacokinetics and relative bioavailability of a generic test formulation and a branded reference formulation of acetylcysteine in fasting healthy Chinese male volunteers. Methods: A single-dose, open-label, randomizedsequence, 2-period crossover design with a 7-day washout period between doses was used in this study. Healthy Chinese male nonsmokers aged 18 to 40 years with a body mass index (BMI) of 19 to 25 kg/m 2 were selected. Eligible volunteers were randomly assigned to receive acetylcysteine 600 mg PO as either the test formulation (3 tablets of 200 mg each) or reference formulation (1 tablet of 600 mg) under fasting conditions. A total of 15 serial blood samples were collected over a 24-hour interval, and total plasma acetylcysteine concentrations were analyzed by a validated liquid chromatographyisotopic dilution mass spectrometry method. Pharmacokinetic parameters (C max, T max, t ½ AUC 0-t, and AUC 0-∞ were calculated and analyzed statistically. The 2 formulations were considered bioequivalent if the 90% CIs of the log-transformed ratios (test/reference) of C max and AUC were within the predetermined bioequivalence ranges (70%–143% for C max; 80%–125% for AUC), as established by the State Food and Drug Administration of China. Tolerability was determined by vital signs, clinical laboratory tests, 12-lead ECGs, physical examinations, and interviews with the subjects about adverse events (AEs). Results: A total of 24 healthy Chinese Han male volunteers were enrolled in and completed the study (mean [SD] age, 25.0 [2.4] years; height, 173.0 [5.6] cm; weight, 65.9 [6.4] kg; BMI, 22.0 [1.7] kg/m 2). No formulation, period, or sequence effects were observed. The 90% CIs for the log-transformed C max, AUC 0-t, and AUC 0-∞ were 89.7% to 103.8%, 86.7% to 101.7%, and 87.7% to 102.4%, respectively, which met the predetermined criteria for assuming bioequivalence. Two subjects (8.3%) experienced 2 mild AEs (increase in total bile acid and prolongation of the QT interval), which were not considered to be related to study drug administration. Conclusions: This single-dose study of acetylcysteine 600 mg PO found that the 3 tablets of the generic test formulation and 1 tablet of the branded reference formulation met the regulatory criteria for assuming bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated