Bioequivalence/bioavailability study of a new formulation of imatinib mesylate 100 mg coated tablets versus Glivec® in Brazilian healthy male volunteers in fed state
DOI:
https://doi.org/10.32635/2176-9745.RBC.2023v69n4.4060Keywords:
imatinib mesylate, therapeutic equivalency, tandem mass spectrometry, tyrosine protein kinase inhibitorsAbstract
Introduction: Imatinib mesylate is currently the first-line oral treatment for all stages of chronic myeloid leukemia (CML) and is also used in some cases of gastrointestinal stromal tumor (GIST) and acute lymphoblastic leukemia (ALL). Objective: Investigate the bioavailability of two products containing imatinib mesylate, 100 mg coated tablet, to determine if they are bioequivalent. Method:
The study was conducted using an open-label, randomized, balanced design and the formulations were administered orally in a single dose to 48 healthy adult males, in fed state, followed by sequential blood withdraws for the next 72 hours. Forty-eight male healthy volunteers were selected to participate in the study. Test formulation from Eurofarma Laboratórios S.A. Brazil was compared to that from Novartis Biociências S.A. The comparative bioavailability of the formulations was assessed based on statistical comparisons of relevant pharmacokinetic parameters obtained from drug concentration data from collected blood samples measured using an analytical method based on high-performance liquid chromatography coupled to mass spectrometry. Results: The ratio of the geometric means between the test and the reference, with a 90% confidence interval, of pharmacokinetic parameters for Cmax was 102.26% (94.17-111.04%) and for AUC0-t was 101.24% (95.19-107.68%). Conclusion: Imatinib mesylate 100 mg (test product) from Eurofarma Laboratórios S.A. was considered bioequivalent to the reference Glivec® 100 mg manufactured by Novartis Biociências S.A, and the test product can be interchangeable with the reference, based on their pharmacokinetic performance.
Downloads
References
An X, Tiwari AK, Sun Y, et al. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34(10):1255-68. DOI: https://doi.org/10.1016/j.leukres.2010.04.016
Kantarjian H, O'Brien S, Jabbour E, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012;119(9):1981-7. DOI: https://doi.org/10.1182/blood-2011-08-358135
Kantarjian HM, Smith TL, O'Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med. 1995;122(4):254-61. DOI: https://doi.org/10.7326/0003-4819-122-4-199502150-00003
Mughal TI, Radich JP, Deininger MW, et al. Chronic myeloid leukemia: reminiscences and dreams. Haematologica. 2016;101(5):541-58. DOI: https://doi.org/10.3324/haematol.2015.139337
Sasaki K, Strom SS, O'Brien S, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. The Lancet Haematology. 2015;2(5):e186-93. DOI: https://doi.org/10.1016/S2352-3026(15)00048-4
Attwood MM, Fabbro D, Sokolov AV, et al. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. 2021;20(11):839-61. DOI: https://doi.org/10.1038/s41573-021-00252-y
Mohajeri E, Kalantari-Khandani B, Pardakhty A, et al. Comparative pharmacokinetic evaluation and bioequivalence study of three different formulations of Imatinib Mesylate in CML patients. Int j hematol. 2015;9:165-72.
Santos SL, Morrone FB. Resultados do mesilato de imatinibe no tratamento da leucemia mielóide crônica: uma revisão bibliográfica. Rev Grad [Internet]. 2008[acesso 2022 fev 17];1(1)1-14. Disponível em: https://revistaseletronicas.pucrs.br/ojs/index.php/graduacao/article/view/2845.
Al-Hadiya BM, Bakheit AH, Abd-Elgalil AA. Imatinib mesylate. Profiles Drug Subst Excip Relat Methodol. 2014;39:265-97. DOI: https://doi.org/10.1016/B978-0-12-800173-8.00006-4
Ostrowicz A, Mikołajczak PL, Wierzbicka M, et al. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers. Acta Pol Pharm. 2014;71(5):843-54.
Jung JA, Kim N, Yang JS, et al. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers. Drug Res (Stuttg). 2014;64(12):651-5. DOI: https://doi.org/10.1055/s-0034-1367059
Kim KA, Park SJ, Kim C, et al. Single-dose, randomized crossover comparisons of different-strength imatinib mesylate formulations in healthy Korean male subjects. Clin Ther. 2013;35(10):1595-602. DOI: https://doi.org/10.1016/j.clinthera.2013.08.008
Jawhari D, AlSwisi M. Bioavailability of a new generic formulation of imatinib mesylate 400mg tablets versus glivec in healthy male adult volunteers. J Bioequiv Availab. 2011;3(7):161-4. DOI: https://doi.org/10.4172/jbb.1000077
Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol Pharm Bull. 2015;38(5):645-54. DOI: https://doi.org/10.1248/bpb.b15-00103
Rezende VM, Rivellis AJ, Gomes MM, et al. Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance. Rev Bras Hematol Hemoter. 2013;35(2):103-8. DOI: https://doi.org/10.5581/1516-8484.20130030
Qian Y, Sun L-N, Liu Y-J, et al. Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors. Front pharmacol. 2019;10:854. doi: https://doi.org/10.3389/fphar.2019.00854 DOI: https://doi.org/10.3389/fphar.2019.00854
Nikolova Z, Peng B, Hubert M, et al. Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules. Cancer Chemother Pharmacol. 2004;53(5):433-8. DOI: https://doi.org/10.1007/s00280-003-0756-z
Ostrowicz A, Miko£ajczak PA, Wierzbicka M, et al. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers. Acta Poloniae Pharmaceutica. 2014;71:843-54.
Pena MA, Muriel J, Saiz-Rodriguez M, et al. Effect of Cytochrome P450 and abcb1 polymorphisms on imatinib pharmacokinetics after single-dose administration to healthy subjects. Clin Drug Investig. 2020;40(7):617-28. DOI: https://doi.org/10.1007/s40261-020-00921-7
Suttorp M, Bornhauser M, Metzler M, et al. Pharmacology and pharmacokinetics of imatinib in pediatric patients. Expert Rev Clin Pharmacol. 2018;11(3):219-31. DOI: https://doi.org/10.1080/17512433.2018.1398644
Abou Dalle I, Kantarjian H, Burger J, et al. Efficacy and safety of generic imatinib after switching from original imatinib in patients treated for chronic myeloid leukemia in the United States. Cancer Med. 2019;8(15):6559-65. DOI: https://doi.org/10.1002/cam4.2545
Vargas M, Villarraga E. Bioequivalence study of imatinib formulations that contain 400 mg in healthy colombians. J Bioequiv Availab. 2017;9(5):483-8.
Glivec(R)® (mesilato de imatinibe) [bula na Internet]. São Paulo: Novartis Biociencias S.A; 2001. Bula de Remédio. [acesso 2022 fev 15]. Disponível em: https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=GLIVEC
Conselho Nacional de Saúde (BR). Resolução n° 466, de 12 de dezembro de 2012. Aprova as diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Diário Oficial da União, Brasília, DF. 2013 jun 13; Seção I:59.
Rezende VM, Rivellis A, Novaes MM, et al. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays. Drug Des Devel Ther. 2013;7:699-710. DOI: https://doi.org/10.2147/DDDT.S42902
O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. DOI: https://doi.org/10.1056/NEJMoa022457
Garcia-Ferrer M, Wojnicz A, Mejia G, et al. Utility of therapeutic drug monitoring of imatinib, nilotinib, and dasatinib in chronic myeloid leukemia: a systematic review and meta-analysis. Clin Ther. 2019;41(12):2558-70. DOI: https://doi.org/10.1016/j.clinthera.2019.10.009
Cole AL, Jazowski SA, Dusetzina SB. Initiation of generic imatinib may improve medication adherence for patients with chronic myeloid leukemia. Pharmacoepidemiol Drug Saf. 2019;28(11):1529-33. DOI: https://doi.org/10.1002/pds.4893
Agência Nacional de Vigilância Sanitária (BR). Resolução RE 1.170 de 19 de Abril de 2006. Diário Oficial da União, Brasília, DF, 2006 abr 24. [acesso 2023 dez 7]. Disponível em: https://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2006/res1170_19_04_2006.html
Published
How to Cite
Issue
Section
License
Os direitos morais e intelectuais dos artigos pertencem aos respectivos autores, que concedem à RBC o direito de publicação.
This work is licensed under a Creative Commons Attribution 4.0 International License.
