Skip to main content

05-31-2017 | SGLT2 inhibitors | Article

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

Journal: Scientific Reports

Authors: Bassam M. Ayoub, Shereen Mowaka, Eman S. Elzanfaly, Nermeen Ashoush, Mohamed M. Elmazar, Shaker A. Mousa

Publisher: Nature Publishing Group UK



The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were Cmax, Tmax, t1/2, elimination rate constant, AUC0-t and AUC0-inf. The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25–600 ng mL−1) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

International Conference on Harmonisation; guidance on ethnic factors in the acceptability of foreign clinical data; availability-FDA. Fed. Reg. 63, 31790–31796 (1998).
Yasuda, S. U., Zhang, L. & Huang, S. M. The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clin. Pharmacol. Ther. 84, 417–423 (2008). CrossRefPubMed
Hansen, H. H. et al. The sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β-cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat. J. Pharm. Exp. Ther. 350, 657–664 (2014). CrossRef
Nair, S. & Wilding, J. P. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J. Clin. Endocrinol. Metab. 95, 34–42 (2010). CrossRefPubMed
Tomlinson, B., Hu, M., Zhang, Y., Chan, P. & Liu, Z. Evaluation of the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin for the treatment of type 2 diabetes. Expert Opin. Drug Metab. Toxicol. 13, 211–223 (2016). CrossRefPubMed
Baron, K. T. et al. Population Pharmacokinetics and Exposure–Response (Efficacy and Safety/Tolerability) of Empagliflozin in Patients with Type 2 Diabetes. Diabetes Ther. 7, 455–471 (2016). CrossRefPubMedPubMedCentral
Macha, S., Brand, T., Meinicke, T., Link, J. & Broedl, U. C. Pharmacokinetics and Pharmacodynamics of Twice Daily and Once Daily Regimens of Empagliflozin in Healthy Subjects. Clin. Ther. 37, 1789–1796 (2015). CrossRefPubMed
Macha, S., Mattheus, M., Pinnetti, S., Broedl, U. C. & Woerle, H. J. Pharmacokinetics of Empagliflozin and Pioglitazone after Coadministration in Healthy Volunteers. Clin. Ther. 37, 1503–1516 (2015). CrossRefPubMed
Zhao, X. et al. Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients with Type 2 Diabetes Mellitus. Clin. Ther. 37, 1493–1502 (2015). CrossRefPubMed
Heise, T., Mattheus, M., Woerle, H. J., Broedl, U. C. & Macha, S. Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: A randomized, open-label, crossover study. Clin. Ther. 37, 793–803 (2015). CrossRefPubMed
Sarashina, A. et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. Clin. Ther. 36, 1606–1615 (2014). CrossRefPubMed
Macha, S. et al. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes. Metab. 16, 215–222 (2014). MathSciNetCrossRefPubMed
Scheen, A. J. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin. Pharmacokinet. 53, 213–225 (2014). CrossRefPubMedPubMedCentral
Macha, S. et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes. Metab. 16, 118–123 (2014). MathSciNetCrossRefPubMed
Macha, S. et al. Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. Clin. Ther. 36, 280–290 (2014). CrossRefPubMed
Kanada, S. et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks’ treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. J. Diabetes Investig 4, 613–617 (2013). CrossRefPubMedPubMedCentral
Riggs, M. M. et al. Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes. J. Clin. Pharmacol. 53, 1028–1038 (2013). CrossRefPubMed
Heise, T. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 15, 613–621 (2013). CrossRefPubMed
Sarashina, A. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. Drug Metab. Pharmacokinet. 28, 213–219 (2013). CrossRefPubMed
Heise, T. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 4, 331–345 (2013). CrossRefPubMedPubMedCentral
Friedrich, C. et al. A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of Empagliflozin and Linagliptin After Coadministration in Healthy Male Volunteers. Clin. Ther. 35, 33–42 (2013). CrossRef
Brand, T., MacHa, S., Mattheus, M., Pinnetti, S. & Woerle, H. J. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv. Ther. 29, 889–899 (2012). CrossRefPubMed
Takanaka, A. A report on recently notified document of clinical pharmacokinetic studies of pharmaceuticals. JPN. J. Clin. Pharmacol. Ther. 32, 217–222 (2001). CrossRef
Food and Drug Administration of the United States, Guidance for Industry Bioanalytical Method Validation, Available at: http://​www.​fda.​gov/​cder/​guidance/​ (accessed October 2016).
Xue, Y. J., Pursley, J. & Arnold, M. E. A simple 96-well liquid-liquid extraction with a mixture of acetonitrile and methyl t-butyl ether for the determination of a drug in human plasma by high-performance liquid chromatography with tandem mass spectrometry. J. Pharm. Biomed. Anal. 34, 369–378 (2004). CrossRefPubMed
Kobuchi, S., Yano, K., Ito, Y. & Sakaeda, T. A validated LC-MS/MS method for the determination of canagliflozin, a sodium–glucose co-transporter 2 (SGLT-2) inhibitor, in a lower volume of rat plasma: application to pharmacokinetic studies in rats. Biomed. Chrom. 30, 1549–1555 (2016). CrossRef
Kobuchi, S., Matsuno, M., Fukuda, E., Ito, Y. & Sakaeda, T. Development and validation of an LC-MS/MS method for the determination of tofogliflozin in plasma and its application to a pharmacokinetic study in rats. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1027, 227–233 (2016). CrossRefPubMed
Kobuchi, S., Ito, Y., Yano, K. & Sakaeda, T. A quantitative LC-MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1000, 22–28 (2015). CrossRefPubMed
Kobuchi, S. et al. A simple and rapid LC-MS/MS method for quantitation of luseogliflozin in rat plasma and its application to a PK study. Bioanalysis 9, 163–171 (2017). CrossRefPubMed
Aubry, A. F. et al. Validated LC-MS/MS methods for the determination of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor in normal and ZDF rat plasma. Bioanalysis 2, 2001–2009 (2010). CrossRefPubMed
Iqbal, M., Ezzeldin, E., Al-Rashood, K. A., Asiri, Y. A. & Rezk, N. L. Rapid determination of canagliflozin in rat plasma by UHPLC-MS/MS using negative ionization mode to avoid adduct-ions formation. Talanta 132, 29–36 (2015). CrossRefPubMed
Zhong, Y. X. et al. Integrated identification, qualification and quantification strategy for pharmacokinetic profile study of Guizhi Fuling capsule in healthy volunteers. Sci. Rep. 6, 31364, doi: 10.​1038/​srep31364 (2016). ADSCrossRefPubMedPubMedCentral
Kudgus, R. A. et al. Tuning pharmacokinetics and biodistribution of a targeted drug delivery system through incorporation of a passive targeting component. Sci. Rep. 4, 5669, doi: 10.​1038/​srep05669 (2014). CrossRefPubMedPubMedCentral
Yang, L. L. et al. Pharmacokinetic comparison between quercetin and quercetin 3- O- β-glucuronide in rats by UHPLC-MS/MS. Sci. Rep. 6, 35460, doi: 10.​1038/​srep35460 (2016). ADSCrossRefPubMedPubMedCentral
Fornasaro, S. et al. Determination of cyanidin 3-glucoside in rat brain, liver and kidneys by UPLC/MS-MS and its application to a short-term pharmacokinetic study. Sci. Rep. 6, 22815, doi: 10.​1038/​srep22815 (2016). ADSCrossRefPubMedPubMedCentral
Gao, Y. et al. Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats. Sci. Rep. 6, 25659, doi: 10.​1038/​srep25659 (2016). ADSCrossRefPubMedPubMedCentral
Alolga, R. N. et al. Pharmacokinetics of a multicomponent herbal preparation in healthy Chinese and African volunteers. Sci. Rep. 5, 12961, doi: 10.​1038/​srep12961 (2015). ADSCrossRefPubMedPubMedCentral
Seman, L. et al. Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Drug Dev. 2, 152–161 (2013). CrossRefPubMed