Bioequivalence Study of Acemetacin Tablets

Abstract

Background and Objective: Acemetacin is a nonsteroidal anti-inflammatory drug (NSAID) structurally derived as a glycolic acid ester of indomethacin, exerting its pharmacological activity through both acemetacin and its primary metabolite, indomethacin. It is indicated for the management of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis, acute musculoskeletal pain, postoperative pain, and dysmenorrhea. The objective of this study was to evaluate and establish the bioequivalence of Acetudil 90 mg Extended Release Capsules (Test; Santa Farma İlaç San. A.Ş, Turkey) with Rantudil® Retard 90 mg Extended Release Capsules (Reference; MEDA Pharma İlaç San. Ve Tic. Ltd. Şti, Turkey) in healthy adult human subjects under fed conditions. Methods: This was an open-label, balanced, randomized, two-treatment, two-sequence, four-period, single-dose, fully replicate crossover bioequivalence study conducted under fed conditions in healthy adult male and/or non-pregnant, non-breastfeeding female volunteers aged 18 to 45 years with a BMI of 18.50–29.99 kg/m². A total of 48 subjects were enrolled, of whom 47 completed the study. A single oral dose of the test or reference product was administered as per the randomization schedule, and serial blood samples were collected over 18 hours post-dose. Plasma concentrations of acemetacin were determined using a validated LC-MS/MS analytical method. Pharmacokinetic parameters were computed using Phoenix® WinNonlin v8.1, and statistical analysis was performed on ln-transformed pharmacokinetic parameters using SAS® v9.4. The primary pharmacokinetic parameters assessed were Cmax and AUC₀₋ₜ. Bioequivalence was concluded if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the test to reference product for both Cmax and AUC₀₋ₜ fell within the pre-specified acceptance range of 80.00–125.00%. Results: The geometric mean ratio (Test/Reference) for ln-transformed Cmax was 95.03% with a 90% CI of 84.51%–106.84%, and for ln-transformed AUC₀₋ₜ was 98.96% with a 90% CI of 94.47%–103.65%, both falling within the pre-defined bioequivalence acceptance criteria of 80.00–125.00%. The intra-subject coefficient of variation (%CV) for Cmax was 44.83% (R vs R) and 46.78% (T vs R), while for AUC₀₋ₜ it was 16.83% (R vs R) and 17.74% (T vs R). Both products were well tolerated; only one non-serious adverse event was reported following administration of the reference product, and no serious adverse events were reported during the conduct of the study. Conclusion: Bioequivalence was successfully demonstrated between Acetudil 90 mg Extended Release Capsules (Test) and Rantudil® Retard 90 mg Extended Release Capsules (Reference) in healthy adult human subjects under fed conditions, with both primary pharmacokinetic parameters meeting the regulatory acceptance criteria. Both formulations were found to be safe and well tolerated at the administered dose.