Glivec to generic imatinib switch: in vitro comparative dissolution assessment, bioequivalence, safety, and tolerability of 400 mg imatinib tablets in healthy volunteers

Abstract

Imatinib is currently considered the “gold standard” pharmacotherapy for chronic myelogenous leukemia (CML) at all stages and is most commonly used in the form of tablets taken orally. The aim of the present study was to perform a quality assessment, bioequivalence study, and safety and tolerability assessment of an investigational test product, imatinib tablets (400 mg), and its comparability with a reference product (Glivec tablets, 400 mg). In vitro dissolution studies of the test and reference products were conducted in three different buffer media (pH 1.2, pH 4.5, and pH 6.8) using Apparatus II (paddle), and the results were compared. The similarity (f₂) factor was calculated to assess in vitro bioequivalence requirements. An open-label, balanced, randomized, two-treatment, two-sequence, two-period, single oral dose, crossover, bioequivalence study was conducted in normal, healthy, adult human subjects under fed conditions. The pharmacokinetic parameters T_max, C_max, AUC_0–t, and AUC_0–∞ were calculated through a non-compartmental model using Phoenix WinNonlin Version 8.3 (Certara L.P.) software. Statistical evaluation and comparison of the two formulations were carried out using PROC GLM in SAS version 9.4 (SAS Institute Inc., USA). The safety profile of the investigational product was monitored during the study by applying a clinical process for recording observed untoward effects post-administration of the investigational product. The investigational test product met USP and BP pharmacopoeial quality standards for in vitro dissolution. Very rapid dissolution (>85% release in 15 minutes) was obtained for the reference and test products in all three buffered dissolution media (pH 1.2, pH 4.5, and pH 6.8) in in vitro dissolution studies. The dissolution profile of the investigational test product (imatinib tablets, 400 mg) was comparable to that of the reference product (Glivec tablets, 400 mg). Furthermore, pharmacokinetic values (C_max, T_max, and AUC) of the test and reference forms of imatinib were similar. Geometric mean ratios (test/reference) for the AUC_0–∞, AUC_0–t, and C_max were 95.2, 0.95.2, and 98.4, respectively. Confidence limits for each of these parameters were in the interval (80.00, 125.00), as were the unadjusted confidence limits. The test and reference formulations of imatinib met the criteria for bioequivalence based on the rate and extent of absorption. Based on the findings of this study, it can be concluded that the test product is bioequivalent and safe, thus suggesting the clinical application of the test product as an alternative to Glivec 400 mg film-coated tablets.