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      Pharmacokinetics and Bioequivalence Evaluation of Two Montelukast Sodium Chewable Tablets in Healthy Chinese Volunteers Under Fasted and Fed Conditions

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          Abstract

          Purpose

          The aim of this study was to assess and compare the pharmacokinetic (PK) properties and bioequivalence of montelukast sodium chewable tablets prepared by two different manufacturers in healthy Chinese volunteers to obtain adequate PK evidence for the registration approval of the test formulation.

          Patients and Methods

          A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR20182362). Eighteen subjects each were selected for a fasted study and a fed study. Eligible participants were randomly assigned in a 1:1 ratio to receive a single dose of the reference formulation or the test formulation, followed by a 5-day washout period and the administration of the alternate formulation. Plasma samples were collected over a 24-hour period following tablet administration and analyzed for montelukast contents by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The PK parameters, such as maximum serum concentration (C max), area under the curve (AUC) from t = 0 to the last quantifiable concentration (AUC 0–t), AUC from t = 0 to infinity (AUC 0–∞), half-life (t 1⁄2), time to C max (T max), and terminal elimination rate constant (λ z), were evaluated. The safety assessment included changes in vital signs (blood pressure, pulse, and temperature) or laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and the incidence of adverse events (AEs).

          Results

          The geometric mean ratios (GMRs) between the two formulations for the primary pharmacokinetic parameters (C max, AUC 0–24, and AUC 0–∞) and the corresponding 90% confidence intervals (Cis) were all within the range of 80.00–125.00% for both the fasting and fed states. The safety profiles for both treatments were comparable.

          Conclusion

          The PK analysis revealed that the test and reference formulations of montelukast sodium chewable tablets were bioequivalent and well-tolerated by healthy Chinese subjects.

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          Most cited references 15

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          Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review.

          To systematically review the evidence for the medium to long term benefits and risks of montelukast as add-on therapy to inhaled corticosteroids (ICS) in comparison with placebo and active controls in mild to moderate asthma. Medline, Embase, Cochrane Register of Controlled Trials, reference lists of retrieved articles, clinical trial registries and study results databases. Systematic review of randomised controlled trials (duration > or = 12 weeks) in adolescents and adults comparing montelukast/ICS versus ICS monotherapy or montelukast/ICS versus active control/ICS. Meta-analyses were conducted where feasible. The main focus was on clinical outcomes (eg, exacerbations). Adverse events were also assessed. 13 studies meeting all of the inclusion criteria were identified: 7 studies, including constant or tapered doses of ICS, compared montelukast/ICS with ICS monotherapy. Six studies compared add-on montelukast with an add-on active control (salmeterol). Overall, the data indicated that montelukast/ICS was clinically more effective than ICS monotherapy. The ICS sparing potential of montelukast was clearly demonstrated in one study. Montelukast/ICS and ICS monotherapy showed similar safety profiles. In the active controlled studies, montelukast/ICS was clinically less effective than salmeterol/ICS in the 12 week trials (pooled proportion of patients with > or = 1 exacerbation: p = 0.006). However, separate analysis of active controlled 48 week trials showed comparable proportions for patients with > or = 1 exacerbation in both groups. Montelukast as add-on therapy to ICS improves control of mild to moderate asthma compared with ICS monotherapy. Although the addition of salmeterol to ICS is clinically as effective as or even more effective than the addition of montelukast, montelukast may have a better long term safety profile and offer a treatment alternative for asthma patients.
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            Clinical effectiveness and safety of montelukast in asthma. What are the conclusions from clinical trials and meta-analyses?

            Asthma is a common childhood atopic disease associated with chronicity and impaired quality of life. As there is no cure for this disease, treatment relies on avoidance of triggers such as food and aeroallergens, the use of inhaled bronchodilators/corticosteroids and antiallergic or immunomodulating therapies. Inhaled corticosteroids (ICSs) and bronchodilators have been the mainstay. However, in Asia, myths and fallacies regarding Western medicine and corticosteroids are prevalent and lead to nonadherence to treatment. Also, use of traditional and proprietary herbal medicines is popular. In the past decades, a novel class of nonsteroidal immunomodulating montelukasts has become available. This article reviews the evidence for the effectiveness and clinical efficacy of these medications. A number of randomized and controlled trials have been performed over the years. The majority of studies confirm the usefulness of montelukast as monotherapy and add-on therapy to ICS in mild to moderate childhood asthma across all age groups. ICSs are generally superior to montelukasts for asthma management. However, montelukast has a place in the treatment of young children with viral-triggered wheezing diseases, exercise-induced asthma, and in children whose parents are steroid-phobic and find ICS unacceptable.
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              CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast.

              According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                09 March 2021
                2021
                : 15
                : 1091-1099
                Affiliations
                [1 ]GCP Office of Cangzhou Central Hospital , Cangzhou, Hebei, 061000, People’s Republic of China
                [2 ]Research Center of Beijing Fuyuan Pharmaceutical Co., Ltd. (Formerly Beijing Wansheng Pharmaceutical Co., Ltd.) , Beijing, 101113, People’s Republic of China
                Author notes
                Correspondence: Weihong Li GCP Office of Cangzhou Central Hospital , No. 16 on Xinhua Road, Cangzhou, Hebei, 061000, People’s Republic of ChinaTel +86 18713731395Fax +86 3172072825 Email sarry610@163.com
                [*]

                These authors contributed equally to this work

                Article
                298355
                10.2147/DDDT.S298355
                7955749
                © 2021 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 13, References: 19, Pages: 9
                Categories
                Original Research

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