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      Is Open Access

      Evaluation of Bioequivalency and Pharmacokinetic Parameters for Two Formulations of Glimepiride 1-mg in Chinese Subjects

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          Abstract

          Purpose

          Glimepiride, an FDA-approved oral hypoglycemic drug, is a long-acting sulfonylurea (SU), used for treating type 2 diabetes. The study aimed to evaluate the bioequivalence and safety profiles of two different formulations of glimepiride 1 mg from two different manufactures in healthy Chinese subjects in the fasting and fed state in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.

          Patients and Methods

          This study is an open-label, two-period, two-sequence, randomized, two-way crossover pharmacokinetic study in healthy Chinese subjects in the fasting and fed state. Seventy-two subjects were randomly assigned to the fasting group and the fed group (n=36 each). We collected blood samples, 24-h post drug administration. The plasma concentration of glimepiride was assessed using HPLC coupled with mass spectrometry. The following parameters were evaluated: AUC 0-inf, AUC 0-last, C max, t 1⁄2, T max, and λ z. Safety was determined based on the occurrence of adverse events (AEs) and laboratory examinations (biochemistry, hematology, and urinalysis) throughout the entire study period.

          Results

          The geometric mean ratios (GMR) amongst the two glimepiride formulations for the primary pharmacokinetic parameters, ie, AUC 0-inf, AUC 0-last, and C max as well as the corresponding 90% CIs, were all within the range of 80.00–125.00% in the fasting and fed state. The safety profile for both treatments was comparable.

          Conclusion

          PK analysis revealed that the test and reference formulations of glimepiride were bioequivalent and well tolerated in healthy Chinese subjects. Chinese Clinical Trials Registry identifier: CTR20171121.

          Clinical Trial Registration Number

          CTR20171121.

          Related collections

          Most cited references 13

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          Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes.

          Glimepiride, a sulfonylurea hypoglycemic agent, is metabolized by cytochrome P450 2C9 (CYP2C9) which is known to have genetic polymorphisms. To examine the effects of CYP2C9 genetic polymorphisms on the safety and efficacy of glimepiride in patients with type 2 diabetes, the responses to the glimepiride were measured in Japanese type 2 diabetic patients with the different CYP2C9 genotype. The reduction in the HbA(1c) was significantly larger (P<0.05) among the CYP2C9*1/*3 subjects than among the CYP2C9*1/*1 subjects. The long-term observations of 2 patients with a CYP2C9*1/*3 suggested that subjects with a CYP2C9*1/*3 respond well to glimepiride during the initial phase of treatment, but 1 patient have shown the weight gain over the long-term treatment. The pharmacokinetic study showed that the area under the concentration-time curve for glimepiride in the CYP2C9*1/*3 subjects was approximately 2.5-fold higher than that of the CYP2C9*1/*1 subjects. The intrinsic clearance of glimepiride by the CYP2C9*3 enzyme was lower than that by the CYP2C9*1 enzyme. These results suggested that the lower hydroxylation activity of glimepiride in the subject with type 2 diabetes and CYP2C9*1/*3 led to a marked elevation in the plasma concentrations of glimepiride and a stronger pharmacological effect of glimepiride.
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            Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs.

            Sulfonylurea drugs including chlorpropamide, gliclazide, tolbutamide, glipizide, glibenclamide (glyburide) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes. This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs. CYP2C9 is the major enzyme involved in sulfonylurea drug metabolism. CYP2C9 variant allele carriers have significant lower apparent clearance of these medicines. CYP2C19 genotype is more influential for gliclazide pharmacokinetics when compared to CYP2C9. Sulfonylurea pharmacodynamics is affected by several genes. Sulfonylurea receptor 1 (SUR1, ABCC8 gene) and K+ inward rectifier Kir6.2 (KCNJ11) have been correlated to significant variation in sulfonylurea response. Diabetics with the SUR1 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the KCNJ11 gene was associated with improved clinical efficacy of gliclazide. Carriers of Transcription factor 7-like 2 (TCF7L2) variants are more likely to fail sulfonylurea therapy. On the other hand, patients with HNF-1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes. The Arg972 polymorphism of insulin receptor substrate 1 (IRS1) may lead to secondary failure of sulfonylurea therapy. Calpain 10 gene (CAPN10) polymorphism has also been linked to sulfonylurea drug response. Despite the available evidence, larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes.
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              Pharmacokinetics of glimepiride and cytochrome P450 2C9 genetic polymorphisms.

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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
                06 July 2020
                2020
                : 14
                : 2637-2644
                Affiliations
                [1 ]School of Pharmacy Lanzhou University, Lanzhou University , Lanzhou, People’s Republic of China
                [2 ]Research Institute, Shandong Xinhua Pharmaceutical Company Limited , Shandong, People’s Republic of China
                [3 ]The Department of Analysis, Chengdu Fanweixi Pharmaceutical Technology Company, Limited , Chengdu, People’s Republic of China
                [4 ]Phase I Clinical Unit, Lanzhou University Second Hospital , Lanzhou, People’s Republic of China
                Author notes
                Correspondence: Wen Qiu Tel/Fax +86-931-8487117 Email qiuwenmm@sina.com
                Article
                249355
                10.2147/DDDT.S249355
                7351633
                © 2020 Ju 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: 4, References: 23, Pages: 8
                Categories
                Clinical Trial Report

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