Bioavailability assessment of fexofenadine and montelukast in a fixed-dose combination tablet versus the components administered simultaneously

Main Article Content

Piñeyro-Garza Everardo
Gómez-Silva Magdalena
Gamino-Peña Maria Elena
Cohen-Muñoz Vanessa
Sánchez-Casado Gabriela

Keywords

fexofenadine, montelukast, bioequivalence, allergic rhinitis, antihistamine-antileukotriene, fixed-dose combination

Abstract

Introduction and Objectives: Allergic rhinitis is a condition with high global prevalence most effectively treated with antihistamines and antileukotrienes. This study aimed to evaluate the bioequivalence of fexofenadine and montelukast in a fixed-dose combination tablet versus the components administered simultaneously.


Materials and Methods: An open, randomized, 2×2 crossover study was performed in 78 healthy volunteers. Fexofenadine–montelukast tablets containing 120 mg and 10 mg, respectively, were used as the test treatment, and 120 mg fexofenadine tablets and 10 mg montelukast tablets were used as the reference treatment. Concentrations of fexofenadine and montelukast in plasma were determined by protein precipitation and analysis by liquid chromatography/mass spectrometry or liquid chromatography tandem mass spectrometry.


Results: The 90% confidence intervals (CIs) obtained for fexofenadine were 87.612–102.144 for area under the curve of the plasma concentration after administration to the last concentration (AUC0-t), 88.471–102.282 for the AUC of the plasma concentration extrapolated to infinity (AUC0–∞), and 91.413–108.544 for the maximum plasma concentration (Cmax). For montelukast, they were 96.418–108.416 for AUC0-t, 93.273–106.642 for AUC0-∞ and 94.749–110.178 for Cmax. The ratio and CIs of the values subjected to logarithmic transformation for each parameter were within the range of acceptability of 80%–125%, demonstrating the bioequivalence of the combined fixed-dose tablet to the components administered separately at the same doses. No adverse events were recorded during the study.


Conclusions: This study has shown the bioequivalence of the combined fixed-dose tablet, which may be considered a new alternative for the treatment of allergic rhinitis.

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References

1. Lehman JM, Blaiss MS. Selecting the optimal oral antihistamine for patients with allergic rhinitis. Drugs. 2006;66:2309–2319. 10.2165/00003495-200666180-00004

2. Cingi C, Gunhan K, Gage-White L, Unlu H. Efficacy of leukotriene antagonists as concomitant therapy in allergic rhinitis. Laryngoscope. 2010;120:1718–1723. 10.1002/lary.20941

3. Çobanoğlu B, Toskala E, Ural A, Cingi C. Role of leukotriene antagonists and antihistamines in the treatment of allergic rhinitis. Curr Allergy Asthma Rep. 2013;13:203–208. 10.1007/s11882-013-0341-4

4. Lagos JA, Marshall GD. Montelukast in the management of allergic rhinitis. Ther Clin Risk Manag. 2007;3:327–332. 10.2147/tcrm.2007.3.2.327

5. Simpson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs. 2000;59:301–321. 10.2165/00003495-200059020-00020

6. Compalati E, Baena-Cagnani R, Penagos M, Badellino H, Braido F, Gómez RM, et al. Systematic review on the efficacy of fexofenadine in seasonal allergic rhinitis: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Int Arch Allergy Immunol. 2011;156:1–15. 10.1159/000321896

7. Naik MM, Nayak A, Khandeparkar P, Mukaddam QI. Efficacy and safety of montelukast plus fexofenadine fixed dose combination in allergic rhinitis: results of post-marketing study in India. Indian Med Gazette. 2013;8:314–318.

8. Mahatme MS, Dakhale GN, Tadke K, Hiware SK, Dudhgaonkar SD, Wankhede S. Comparison of efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine in patients of allergic rhinitis: a randomized, double-blind clinical trial. Indian J Pharmacol. 2016;48:649–653. 10.4103/0253-7613.194854

9. Gupta V, Matreja PS. Efficacy of montelukast and levocetirizine as treatment for allergic rhinitis. J Aller Ther. 2010;1:103. 10.4172/2155-6121.1000103

10. Ciebiada M, Gorska-Ciebiada M, Gorski P. Fexofenadine with either montelukast or a low-dose inhaled corticosteroid (fluticasone) in the treatments of patients with persistent allergic rhinitis and newly diagnosed asthma. Arch Med Sci. 2009;5:564–569.

11. Walekar A, Chodankar D, Naqvi M, Trivedi C. Assessment of bioequivalence of fexofenadine and montelukast fixed dose combination tablet versus separate formulations of the individual components at the same dose levels. Indian J Pharm Sci. 2017;78:651–656. 10.4172/pharmaceutical-sciences.1000164

12. Mendoza L, Begany P, Dyrhonova M, Emritte N, Svobodova X. Bioequivalence of two fexofenadine formulations in healthy human volunteers after single oral administration. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007;151:65–67. 10.5507/bp.2007.011

13. Public assessment report decentralised procedure MONTELUKAST 10MG film-coated tablets UK/H/2199/001/DC UK licence no: PL 04416/0946 Sandoz Limited. https://mri.cts-mrp.eu/human/downloads/DE_H_5912_001_PAR.pdf. Available at: Last accessed April 2021.

14. Luo J, Imai H, Ohyama T, Hashimoto S, Hasunuma T, Inoue Y, et al. The pharmacokinetic exposure to fexofenadine is volume-dependently reduced in healthy subjects following oral administration with apple juice. Clin Transl Sci. 2016;9:201–206. 10.1111/cts.12400

15. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2011. Available at: http://www.R-project.org/.

16. Bolton S, Bon C. Pharmaceutical statistics: practical and clinical applications. 4th ed., rev.expanded. New York: M. Dekker; 2004.

17. Westlake WJ. Symmetrical confidence intervals for bioequivalence trials. Biometrics. 1976;32:741–744. 10.2307/2529259

18. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–680. 10.1007/BF01068419

19. Chow S-C, Liu J. Design and analysis of bioavailability and bioequivalence studies. 3rd ed. Boca Raton, FL: CRC Press; 2009.

20. European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on the investigation of bioequivalence. 2010. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf.

21. Secretaría de Salud, Comisión Federal para la Protección de riesgos Sanitarios. Norma Oficial Mexicana NOM-177-SSA1-2013. Diario Oficial de la Federación. Available at: http://www.dof.gob.mx/nota_detalle.php?codigo=5314833&fecha=20/09/2013. Published September 20, 2013.