دورية أكاديمية
Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption.
العنوان: | Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption. |
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المؤلفون: | Ping X; Basic Teaching Department, Baoding Technical College of Electric Power, Baoding, Hebei, China., Wang G; Zhongcai Health (Beijing) Biological Technology Development Co., Ltd, Beijing, China., Gao D; Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China. |
المصدر: | Journal of clinical pharmacology [J Clin Pharmacol] 2024 Jun; Vol. 64 (6), pp. 672-684. Date of Electronic Publication: 2024 Feb 16. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2013- : Oxford : Wiley Original Publication: Stamford, Conn., Hall Associates. |
مواضيع طبية MeSH: | Glucosides*/pharmacokinetics , Benzhydryl Compounds*/pharmacokinetics , Benzhydryl Compounds*/urine , Sodium-Glucose Transporter 1*/metabolism , Models, Biological* , Sodium-Glucose Transporter 2 Inhibitors*/pharmacokinetics , Sodium-Glucose Transporter 2 Inhibitors*/pharmacology, Humans ; Glucose/metabolism ; Male ; Sodium-Glucose Transporter 2/metabolism ; Adult ; Hypoglycemic Agents/pharmacokinetics ; Hypoglycemic Agents/pharmacology ; Renal Reabsorption/drug effects ; Kidney/metabolism ; Glycosuria ; Female ; Middle Aged |
مستخلص: | The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na + reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP. (© 2024, The American College of Clinical Pharmacology.) |
References: | Jitraknatee J, Ruengorn C, Nochaiwong S. Prevalence and risk factors of chronic kidney disease among type 2 diabetes patients: a cross‐sectional study in primary care practice. Sci Rep. 2020;10(1):6205. Choi C‐I. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next‐generation antihyperglycemic agents. Molecules. 2016;21(9):1136. Jaikumkao K, Pongchaidecha A, Chatsudthipong V, Chattipakorn SC, Chattipakorn N, Lungkaphin A. The roles of sodium‐glucose cotransporter 2 inhibitors in preventing kidney injury in diabetes. Biomed Pharmacother. 2017;94:176‐187. Ndefo UA, Anidiobi NO, Basheer E, Eaton AT. Empagliflozin (Jardiance): a novel SGLT2 inhibitor for the treatment of type‐2 diabetes. P T. 2015;40(6):364. Boehringer Ingelheim Pharmaceuticals. JARDIANCE (empagliflozin tablet): prescribing information. Accessed November 26, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a‐9cd0‐39c2‐0d2e‐232cb3f67565. Chen L‐Z, Jungnik A, Mao Y, et al. Biotransformation and mass balance of the SGLT2 inhibitor empagliflozin in healthy volunteers. Xenobiotica. 2015;45(6):520‐529. Fu Y, Breljak D, Onishi A, et al. Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin. Am J Physiol. 2018;315(2):F386‐F394. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter‐2 (SGLT‐2) inhibitor: characterisation and comparison with other SGLT‐2 inhibitors. Diabetes Obes Metab. 2012;14(1):83‐90. Heise T, Seman L, Macha S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013;4:331‐345. Lu Y, Griffen SC, Boulton DW, Leil TA. Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans. Front Pharmacol. 2014;5:274. Wang Z, Wang G, Ren J. Using a mathematical modeling to simulate pharmacokinetics and urinary glucose excretion of luseogliflozin and explore the role of SGLT1/2 in renal glucose reabsorption. ACS Omega. 2022;7(51):48427‐48437. Samukawa Y, Mutoh M, Chen S, Mizui N. Mechanism‐based pharmacokinetic–pharmacodynamic modeling of luseogliflozin, a sodium glucose co‐transporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. Biol Pharm Bull. 2017;40(8):1207‐1218. Balazki P, Schaller S, Eissing T, Lehr T. A quantitative systems pharmacology kidney model of diabetes associated renal hyperfiltration and the effects of SGLT inhibitors. CPT Pharmacometrics Syst Pharmacol. 2018;7(12):788‐797. Yakovleva T, Sokolov V, Chu L, et al. Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: a quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors. Diabetes Obes Metab. 2019;21(12):2684‐2693. Mori‐Anai K, Tashima Y, Nakada T, Nakamaru Y, Takahata T, Saito R. Mechanistic evaluation of the effect of sodium‐dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics. Biopharm Drug Dispos. 2020;41(8‐9):352‐366. Zhang Y, Xie P, Li Y, Chen Z, Shi A. Mechanistic evaluation of the inhibitory effect of four SGLT‐2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches. Front Pharmacol. 2023;14:1142003. Pharmaceuticals and Medical Devices Agency (PMDA). Accessed November 26, 2023. https://www.info.pmda.go.jp/go/interview/1/650168_3969023F1023_1_227_1F.pdf. Food and Drug Administration (FDA). Accessed November 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000ClinPharmR.pdf. Xiao J, Tran D, Zhang X, et al. Biliary excretion‐mediated food effects and prediction. AAPS J. 2020;22:1‐10. Wang Z, Liu W, Li X, et al. Physiologically based pharmacokinetic combined JAK2 occupancy modelling to simulate PK and PD of baricitinib with kidney transporter inhibitors and in patients with hepatic/renal impairment. Regul Toxicol Pharmacol. 2022;133:105210. Tahara A, Takasu T, Yokono M, Imamura M, Kurosaki E. Characterization and comparison of sodium‐glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci. 2016;130(3):159‐169. Macha S, Koenen R, Sennewald R, et al. Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. Clin Ther. 2014;36(2):280‐290.e1. Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter‐mediated drug‐drug interactions for baricitinib. Clin Transl Sci. 2017;10(6):509‐519. Brand T, Macha S, Mattheus M, Pinnetti S, Woerle HJ. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter‐2 (SGLT‐2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther. 2012;29:889‐899. Friedrich C, Metzmann K, Rose P, Mattheus M, Pinnetti S, Woerle HJ. A randomized, open‐label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther. 2013;35(1):A33‐A42. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle H, Broedl U. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16(3):215‐222. Heise T, Seewaldt‐Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613‐621. Macha S, Rose P, Mattheus M, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014;16(2):118‐123. Macha S, Brand T, Meinicke T, Link J, Broedl UC. Pharmacokinetics and pharmacodynamics of twice daily and once daily regimens of empagliflozin in healthy subjects. Clin Ther. 2015;37(8):1789‐1796. Macha S, Mattheus M, Pinnetti S, Broedl UC, Woerle HJ. Pharmacokinetics of empagliflozin and pioglitazone after coadministration in healthy volunteers. Clin Ther. 2015;37(7):1503‐1516. Li X, Frechen S, Moj D, et al. A physiologically based pharmacokinetic model of voriconazole integrating time‐dependent inhibition of CYP3A4, genetic polymorphisms of CYP2C19 and predictions of drug–drug Interactions. Clin Pharmacokinet. 2020;59:781‐808. Vallon V, Rose M, Gerasimova M, et al. Knockout of Na‐glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol. 2013;304(2):F156‐F167. Wang XX, Levi J, Luo Y, et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem. 2017;292(13):5335‐5348. Liu J, Lee T, DeFronzo RA. Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans? Diabetes. 2012;61(9):2199‐2204. Abdul‐Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62(10):3324‐3328. |
فهرسة مساهمة: | Keywords: PBPK model; SGLT1 compensation; SGLT2 occupancy; UGE; empagliflozin |
المشرفين على المادة: | HDC1R2M35U (empagliflozin) 0 (Glucosides) 0 (Benzhydryl Compounds) 0 (Sodium-Glucose Transporter 1) 0 (Sodium-Glucose Transporter 2 Inhibitors) 0 (SLC5A1 protein, human) IY9XDZ35W2 (Glucose) 0 (Sodium-Glucose Transporter 2) 0 (Hypoglycemic Agents) 0 (SLC5A2 protein, human) |
تواريخ الأحداث: | Date Created: 20240216 Date Completed: 20240527 Latest Revision: 20240604 |
رمز التحديث: | 20240604 |
DOI: | 10.1002/jcph.2413 |
PMID: | 38363006 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1552-4604 |
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DOI: | 10.1002/jcph.2413 |