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Shen C, Xie H, Jiang X, Wang L. A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment. J Pharmacokinet Pharmacodyn 2025; 52:13. [PMID: 39821812 DOI: 10.1007/s10928-025-09961-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/08/2025] [Indexed: 01/19/2025]
Abstract
Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose. Based on the optimization of renal function-dependent parameters, the model was extrapolated to different stages renal impairment patients. Ultimately our model adequately describes the pharmacokinetics of alogliptin, the progression of DPP-4 inhibition over time and the dynamics of the glucose control system components. The extrapolation results endorse the dose adjustment regimen of 12.5 mg once daily for moderate patients and 6.25 mg once daily for severe and ESRD patients, while providing additional reflections and insights. In clinical practice, our model could provide additional information on the in vivo fate of DPP4 inhibitors and key regulators of the glucose control system.
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Affiliation(s)
- Chaozhuang Shen
- Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Haitang Xie
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, 241001, China
| | - Xuehua Jiang
- Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Ling Wang
- Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu, 610064, China.
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Pelluri R, Kongara S, Nagasubramanian VR, Mahadevan S, Chimakurthy J. Effect of Teneligliptin 20 mg Twice Daily on Glucagon-Like Peptide-1 Levels and Its Influence on Non-Glycemic Components in Non-Diabetic Obese Individuals. Metab Syndr Relat Disord 2024; 22:90-96. [PMID: 38165660 DOI: 10.1089/met.2023.0218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2024] Open
Abstract
Background and Aims: Teneligliptin is an oral antidiabetic agent, it can persevere glucagon-like peptide-1 (GLP-1) by inhibiting dipeptidyl peptidase enzyme. In addition, it has rare incidence of hypoglycemia. Hence, this study aimed to test the effect of teneligliptin 20 mg twice daily along with low carbohydrate diet and physical exercise on change of body weight and insulin resistance in nondiabetic obese subjects. Materials and Methods: It is a prospective, randomized, double-blind, placebo-controlled, parallel group study carried out at outpatient department of an endocrinology hospital over the period of 48 weeks. Teneligliptin 20 mg twice daily 30 min before food (low carbohydrate diet [LCD]) with regular physical exercise, and control group was kept with placebo twice daily 30 min before food LCD with regular physical exercise. This study was registered in clinical trial registry of India [CTRI/2020/02/023329]. Results: A total of 150 nondiabetic obese subjects were randomized into test (n = 75) and control groups (n = 75). At the end of 48 weeks there was significant improvement in GLP-1, simplified nutrition assessment questionnaire (SNAQ) score, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and body weight. The mean difference and 95% confidence interval of GLP-1 (pg/mL) was 76.42 (44.42-148.41) (P = 0.37); SNAQ score, -1.64 (-2.48 to -0.81) (P = 0.000); HOMA-IR, -0.9 (-0.59 to -0.38) (P = 0.000); TG (mg/dL) -29.37 (-44.46 to -14.07) (P = 0.000); reduction of body weight (kilograms) -3.09 (-6.11 to -0.07) (P = 0.043). Conclusion: Findings of this study reveals that teneligliptin-treated group showed significant improvement in GLP-1 levels, reduced insulin resistance, body weight, TG, appetite, and metabolic syndrome. Teneligliptin is well tolerated, except in upper respiratory tract infections. CTR number: CTRI/2020/02/023329.
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Affiliation(s)
- Ranakishor Pelluri
- Department of Pharmacy Practice, Sri Ramachandra Institute of Higher Education Research, (Deemed to be University), Chennai, India
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
| | - Srikanth Kongara
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
| | | | - Shriraam Mahadevan
- Department of Endocrinology and Metabolism, Sri Ramachandra Institute of Higher Education and Research, (Deemed to be University), Chennai, India
| | - Jithendra Chimakurthy
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
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Li Q, Deng X, Xu YJ, Dong L. Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants. J Med Chem 2023; 66:11593-11631. [PMID: 37647598 DOI: 10.1021/acs.jmedchem.3c00412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of long-acting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
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Affiliation(s)
- Qing Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xiaoyan Deng
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Yan-Jun Xu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Lin Dong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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Attia KAM, Abdel-Monem AH, Ashmawy AM, Eissa AS, Abdel-Raoof AM. Construction and application of highly sensitive spinel nanocrystalline zinc chromite decorated multiwalled carbon nanotube modified carbon paste electrode (ZnCr 2O 4@MWCNTs/CPE) for electrochemical determination of alogliptin benzoate in bulk and its dosage form: green chemistry assessment. RSC Adv 2022; 12:19133-19143. [PMID: 35865580 PMCID: PMC9245611 DOI: 10.1039/d2ra02685f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/23/2022] [Indexed: 11/21/2022] Open
Abstract
A new sensor for alogliptin benzoate (ALG) estimation based on a simple and sensitive method was evolved on multiwalled-carbon-nanotube modified nanocrystalline zinc chromite carbon paste electrodes (ZnCr2O4@MWCNTs/CPEs). ALG electrochemical behavior was evaluated using a cyclic voltammetry (CV), square wave voltammetry (SWV) and chronoamperometry (CA). The new electrode materials were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), energy dispersive X-ray analysis (EDX) for elemental analysis and mapping, and X-ray diffraction (XRD) and the X-ray photoelectron spectroscopy (XPS) measurements. All these measurements exhibiting enhanced activity and high conductivity compared to the bare electrode without modification. The calibration curves obtained for ALG were in the ranges of 0.1-20 μmol L-1 with a quantification and detection limits of 0.09 and 0.03 μmol L-1, respectively. The prepared sensor showed a good sensitivity and selectivity with less over potential for ALG determination. Finally, the presented method was successfully applied as a simple, precise and selective electrochemical electrode for the estimation of ALG in its pharmaceutical dosage form.
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Affiliation(s)
- Khalid A M Attia
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University 11751 Nasr City Cairo Egypt
| | - Ahmed H Abdel-Monem
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University 11751 Nasr City Cairo Egypt
| | - Ashraf M Ashmawy
- Chemistry Department, Faculty of Science, Al-Azhar University Nasr City Cairo 11884 Egypt
| | - Amr S Eissa
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University Badr 11829 City Cairo Egypt
| | - Ahmed M Abdel-Raoof
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University 11751 Nasr City Cairo Egypt
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Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules 2022; 27:3055. [PMID: 35630534 PMCID: PMC9147686 DOI: 10.3390/molecules27103055] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.
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Affiliation(s)
| | | | | | | | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China; (R.Y.); (Y.X.); (X.W.); (L.Y.)
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Khotimchenko M, Brunk NE, Hixon MS, Walden DM, Hou H, Chakravarty K, Varshney J. In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome. Pharm Res 2022; 39:2937-2950. [PMID: 35313359 DOI: 10.1007/s11095-022-03231-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/10/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes. METHODS Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions. RESULTS Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult. CONCLUSIONS Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.
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Affiliation(s)
- Maksim Khotimchenko
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Nicholas E Brunk
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Mark S Hixon
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Daniel M Walden
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Hypatia Hou
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Kaushik Chakravarty
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA.
| | - Jyotika Varshney
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA.
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Pan Q, Yuan M, Guo L. Exposure-Response Analysis of Cardiovascular Outcome Trials With Incretin-Based Therapies. Front Endocrinol (Lausanne) 2022; 13:893971. [PMID: 35721733 PMCID: PMC9204533 DOI: 10.3389/fendo.2022.893971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/22/2022] [Indexed: 11/17/2022] Open
Abstract
Our study aimed to evaluate the exposure-response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log Cmax, log AUC0-24h, and log AUCCVOT are negatively correlated with MACE HR (R2 = 0.8494, R2 = 0.8728, and R2 = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log Cmax, log AUC0-24h, and log AUCCVOT) and MACE HR strongly corresponded with the log (inhibitor) vs. response curve (R2 = 0.8383, R2 = 0.8430, and R2 = 0.8229, respectively). The cutoff values in the ROC curves for log Cmax, log AUC0-24h, and log AUCCVOT, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher's exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure-response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure.
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Affiliation(s)
- Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, China
| | - Mingxia Yuan
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, China
- *Correspondence: Lixin Guo,
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Wang L, Lu J, Zhou S, Zhao Y, Xie L, Zhou C, Chen J, Ding S, Xie D, Ding J, Yu Q, Shen H, Hao G, Shao F. First-in-Human, Single-Ascending Dose and Food Effect Studies to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Cetagliptin, a Dipeptidyl Peptidase-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. Clin Drug Investig 2021; 41:999-1010. [PMID: 34655432 DOI: 10.1007/s40261-021-01088-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND OBJECTIVES Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. METHODS Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. RESULTS Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. CONCLUSIONS Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. CLINICAL TRIAL REGISTRATION The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).
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Affiliation(s)
- Lu Wang
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jinmiao Lu
- CGeneTech (Suzhou, China) Co., Ltd, Suzhou, Jiangsu, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Sufeng Zhou
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Yuqing Zhao
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Lijun Xie
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Chen Zhou
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Juan Chen
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Sijia Ding
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Daosheng Xie
- Beijing Noahpharm Medical Technology Co., Ltd, Beijing, China
| | - Juping Ding
- CGeneTech (Suzhou, China) Co., Ltd, Suzhou, Jiangsu, China
| | - Qiang Yu
- CGeneTech (Suzhou, China) Co., Ltd, Suzhou, Jiangsu, China
| | - Hong Shen
- Beijing Scinovo Laboratories Ltd, Beijing, China
| | - Guangtao Hao
- Beijing Scinovo Laboratories Ltd, Beijing, China
| | - Feng Shao
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Tomlinson B, Chan P, Lam CWK. An overview of alogliptin + pioglitazone for the treatment of type 2 diabetes. Expert Opin Pharmacother 2021; 23:29-42. [PMID: 34591742 DOI: 10.1080/14656566.2021.1985465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is a progressive condition, and sequential additions of therapy are usually required to maintain glycemic control. The options for glucose lowering therapies have increased considerably in recent years. Fixed-dose combinations such as alogliptin with pioglitazone provide a convenient choice which can improve medication adherence. AREAS COVERED The authors performed a literature search to identify publications describing the efficacy and safety of alogliptin and pioglitazone when used separately and in combinations. EXPERT OPINION Pioglitazone activates peroxisome proliferator-activated receptor-gamma which improves insulin sensitivity and helps to preserve β-cell function with a durable improvement in glycemic control. Pioglitazone can retard the progression of atherosclerosis and reduce cardiovascular events, but it is associated with adverse events including weight gain, fluid retention, and increased risk of fractures. Alogliptin improves glycemic control and appears neutral in terms of cardiovascular events. It does not appear to increase the adverse events associated with pioglitazone and use of the combination may permit the use of lower doses of pioglitazone with reduced adverse effects. There are no cardiovascular outcome studies with the combination but the cardiovascular benefits of pioglitazone and additional glucose lowering effects of alogliptin provide a useful combination with convenient once daily dosing.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Paul Chan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
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Morimoto K, Sasaki M, Oikawa E, Abe M, Kikuchi T, Ishii M, Ogihara T, Tomita M. Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter. Biol Pharm Bull 2021; 44:653-658. [PMID: 33952821 DOI: 10.1248/bpb.b20-00947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.
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Affiliation(s)
- Kaori Morimoto
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Momona Sasaki
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Erika Oikawa
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Maho Abe
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Tatsuro Kikuchi
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Makoto Ishii
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Takuo Ogihara
- Graduate School of Pharmaceutical Science, Takasaki University of Health and Welfare
| | - Mikio Tomita
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
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12
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Zhang S, Gan R, Zhao L, Sun Q, Xiang H, Xiang X, Zhao G, Li H. Unveiling the interaction mechanism of alogliptin benzoate with human serum albumin: Insights from spectroscopy, microcalorimetry, and molecular docking and molecular dynamics analyses. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 246:119040. [PMID: 33068900 DOI: 10.1016/j.saa.2020.119040] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/23/2020] [Accepted: 10/01/2020] [Indexed: 06/11/2023]
Abstract
The interaction between a DPP-4 inhibitor, alogliptin benzoate (AB), and human serum albumin (HSA) was systematically investigated via spectroscopy, microcalorimetry and molecular simulations. Steady-state fluorescence and time-resolved fluorescence spectrometry illustrated that the fluorescence quenching type of AB to HSA was static and caused by the formation of ground state AB-HSA complex. Isothermal titration calorimetry (ITC) combined with fluorescence spectra revealed that the affinity of AB to the subdomain IIA of HSA was moderate with a binding constant in the order of 104. Molecular docking analysis and thermodynamic parameters demonstrated that this combination was maintained by hydrogen bonding along with van der Waals force and hydrophobic force. Circular dichroism and three-dimensional (3D) fluorescence showed that AB increased the hydrophobicity of Trp residue and the α-helix content of HSA by 1.99%. Microdifferential scanning calorimetry revealed that the addition of AB enhanced the thermal stability of HSA. The action forces, binding stability, binding sites, and protein structure of the AB-HSA system were evaluated via molecular dynamics analysis in the simulated environment. On the basis of molecular docking, MD simulation constructed a more reliable 3D model of the AB-HSA complex in terms of spatial structure.
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Affiliation(s)
- Shuangshuang Zhang
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
| | - Ruixue Gan
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
| | - Ludan Zhao
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
| | - Qiaomei Sun
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China.
| | - Hongzhao Xiang
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
| | - Xi Xiang
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
| | - Gang Zhao
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China.
| | - Hui Li
- School of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China
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13
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Salting-out induced liquid-liquid microextraction for alogliptin benzoate determination in human plasma by HPLC/UV. BMC Chem 2021; 15:2. [PMID: 33451337 PMCID: PMC7809805 DOI: 10.1186/s13065-020-00729-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/10/2020] [Indexed: 01/22/2023] Open
Abstract
Salting-out induced liquid–liquid microextraction method has been developed for plasma sample treatment before determination of alogliptin by high performance liquid chromatography with UV detection. Several parameters were optimized to achieve maximum enrichment, including type of extractant, volume of extractant, type of anion, type of cation, salt amount and pH. The optimum conditions were attained using 500 µL of acetonitrile, added to 1 mL of aqueous sample containing 250 mg of sodium chloride at pH 12. An RP-HPLC method was developed and validated according to the International Conference on Harmonization guidelines M10. The method was linear in the concentration range of 0.1 to 50 µg/mL (correlation coefficient = 0.997). The limit of detection was 0.019 µg/mL and limit of quantitation was 0.06 µg/mL. The method was accurate and precise with an average % recovery of 99.7% and a % relative standard deviation ranging between 1.5 and 2.5. These results showed that the salting-out induced liquid–liquid microextraction methods could be better than other sample preparation protocols in terms of sensitivity, easiness, solvent consumption and waste reduction.
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14
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Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:642-653. [PMID: 32929230 DOI: 10.1038/s41574-020-0399-8] [Citation(s) in RCA: 210] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2020] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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15
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The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. Int J Mol Sci 2020; 21:ijms21165756. [PMID: 32796688 PMCID: PMC7460951 DOI: 10.3390/ijms21165756] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 01/02/2023] Open
Abstract
Despite a similar mechanism of action underlying their glucose-lowering effects in type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. To explore the issue of possible DPP-4 inhibitor cardiac heterogeneity, we perfused different DPP-4 inhibitors to beating mouse hearts ex vivo, at concentrations equivalent to peak plasma levels achieved in humans with standard dosing. We studied male and female mice, young non-diabetic mice, and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin, and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Furthermore, linagliptin increased cardiomyocyte cGMP when cells were co-cultured with C166 endothelial cells, but not when cardiomyocytes were cultured alone. Thus, at a concentration comparable to that achieved in patients, linagliptin has direct effects on mouse hearts. The effects of linagliptin on cardiomyocytes are likely to be either off-target or indirect, mediated through NO generation by the adjacent cardiac endothelium.
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16
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Yamamoto Y, Yamamoto Y, Saita T, Hira D, Chijiwa T, Shin M. Immunohistochemical Pharmacokinetics of the Anti-diabetes Drug Alogliptin in Rat Kidney and Liver. Acta Histochem Cytochem 2020; 53:55-60. [PMID: 32624630 PMCID: PMC7322161 DOI: 10.1267/ahc.19036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 04/30/2020] [Indexed: 01/09/2023] Open
Abstract
Alogliptin is one of a new class of therapeutic agents for type 2 diabetes called dipeptidyl peptidase-4 inhibitors. Here, we used immunohistochemistry to investigate the pharmacokinetics of alogliptin at the cell and tissue levels in the rat kidney and liver. One hour after alogliptin administration, the most noticeable immunoreactivity in the kidney was a moderate-to-strong staining in proximal tubule S3 segment epithelial cells. On the other hand, immunostaining was found only in the microvilli of S1 and S2 segment cells. Immunoreactivity was also observed in the glomerulus and distal tubules. Positive cells and almost negative cells coexisted in the collecting ducts. Twenty-four hours after administration, moderate immunostaining remained in the S3 segment but staining in other regions had almost disappeared. In the liver 1 hr after administration, hepatocyte staining differed in the hepatic lobule, with zone III being stronger than zone I. Immunostaining had almost disappeared 24 hr after administration. These findings suggest that alogliptin reabsorption at the kidney and uptake at the hepatocyte vary from region to region and that one or more types of transporter are involved in these processes. In addition, long-term alogliptin use may cause the drug to accumulate in S3 segment, leading to adverse events.
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Affiliation(s)
- Yutaro Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
| | - Yuta Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
| | - Tetsuya Saita
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
| | - Daisuke Hira
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
| | - Takahito Chijiwa
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
| | - Masashi Shin
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, 4–22–1 Ikeda, Nishi-ku, Kumamoto 860–0082, Japan
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17
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Kelani KM, Rezk MR, Badran OM, Elghobashy MR. Determination of pioglitazone, its metabolite and alogliptin in human plasma by a novel LC-MS/MS method; application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1132:121803. [DOI: 10.1016/j.jchromb.2019.121803] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/10/2019] [Accepted: 09/11/2019] [Indexed: 11/28/2022]
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Hu J, Yang C, Wang H, Li J, Tan X, Wang J, Zhang B, Zhao Y. An up-to-date evaluation of alogliptin benzoate for the treatment of type 2 diabetes. Expert Opin Pharmacother 2019; 20:1679-1687. [PMID: 31335214 DOI: 10.1080/14656566.2019.1645124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.
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Affiliation(s)
- Jingbo Hu
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
| | - Chunlin Yang
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Hongbo Wang
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Jing Li
- Department of pharmacy, Ningbo University affiliated Yangming Hospital , Yuyao , China
| | - Xueying Tan
- College of pharmacy, Zhejiang Pharmaceutical College , Ningbo , China
| | - Jinhui Wang
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and Pharmaceutical Sciences, Ningbo University , Ningbo , China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University , Ningbo , China
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Attallah MA, Mowaka S, Elkady EF, Fouad M, Ayoub B. Analysis and bio-analysis of omarigliptin, trelagliptin and alogliptin: Applied to biological samples and degradation kinetic study. Microchem J 2019. [DOI: 10.1016/j.microc.2019.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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20
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Gou ZP, Wang ZL, Liang XF, Zheng L, Wang Y, Feng P. Single-dose escalation study of yogliptin in healthy Chinese volunteers. Eur J Pharm Sci 2019; 136:104950. [PMID: 31173870 DOI: 10.1016/j.ejps.2019.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/12/2019] [Accepted: 06/03/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed. METHODS A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay. RESULTS A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (Tmax) of 3.0 h and was eliminated slowly with a t1/2 of 25.45-43.84 h. The maximum observed concentration (Cmax) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg. CONCLUSION Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. TRIAL REGISTRATION ChiCTR-IIR-17010311 (Chictr.org).
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Affiliation(s)
- Zhong-Ping Gou
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Zhen-Lei Wang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Xiu-Fang Liang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Li Zheng
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ying Wang
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ping Feng
- Institute of Drug Clinical Trials, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
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Kant R, Bodla RB, Bhutani R, Kapoor G. Enantioselective Box Behenken Optimized HPLC-DAD Method for the Simultaneous Estimation of Alogliptin Enantiomorphs in Pharmaceutical Formulations and their Pharmacokinetic Study in Rat Plasma. Adv Pharm Bull 2019; 9:147-158. [PMID: 31011569 PMCID: PMC6468233 DOI: 10.15171/apb.2019.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 10/02/2018] [Accepted: 12/20/2018] [Indexed: 11/18/2022] Open
Abstract
Purpose: A stereoselective high performance liquid chromatographic analytical method with
photodiode array detector was developed and validated as per the International Conference
on Harmonization (ICH) guidelines for the determination of alogliptin (ALO) enantiomers in
formulations and rat plasma.
Methods: Enantiomeric separation was performed on a Phenomenex Lux Cellulose-2 chiral
column. Box-Behnken design was used to identify the optimum conditions of the three
independent variables for the desired output responses.
Results: The HPLC peaks of ALO enantiomers and the internal standard pioglitazone were
achieved before 8 min with a resolution of 0.77 min between R and S enantiomer and resolution
of more than 2.0 between each enantiomer and pioglitazone (internal) with more than 95%
recovery. The linearity range and the limit of quantification of both the enantiomers in rat plasma
were 10-70 ng mL-1 and 1.2 ng mL-1 respectively.
Conclusion: The developed method after validation was successfully applied for estimation of ALO enantiomers in formulations. Single oral dose of 25 mg of the ALO racemate tablets were
administered to a group of 6 healthy rats for a comparative pharmacokinetic study of both the
enantiomers.
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Affiliation(s)
- Ravi Kant
- Pharmaceutical Chemistry Department, Delhi Institute of Pharmaceutical Sciences & Research, University of Delhi, Sector 3 Pushp Vihar, Mehrauli Badarpur Road, New Delhi -110017, India
| | - Ramesh Babu Bodla
- Pharmaceutical Chemistry Department, Delhi Institute of Pharmaceutical Sciences & Research, University of Delhi, Sector 3 Pushp Vihar, Mehrauli Badarpur Road, New Delhi -110017, India
| | - Rubina Bhutani
- Pharmaceutical Chemistry Department, Delhi Institute of Pharmaceutical Sciences & Research, University of Delhi, Sector 3 Pushp Vihar, Mehrauli Badarpur Road, New Delhi -110017, India
| | - Garima Kapoor
- Pharmaceutical Chemistry Department, Delhi Institute of Pharmaceutical Sciences & Research, University of Delhi, Sector 3 Pushp Vihar, Mehrauli Badarpur Road, New Delhi -110017, India
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Yamamoto Y, Yamamoto Y, Saita T, Shin M. Immunohistochemistry for Anti-diabetes Drug, Alogliptin Using a Newly Prepared Monoclonal Antibody: Its Precise Localization in Rat Small Intestine. Acta Histochem Cytochem 2019; 52:27-34. [PMID: 30923413 PMCID: PMC6434317 DOI: 10.1267/ahc.18036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/10/2019] [Indexed: 12/17/2022] Open
Abstract
Knowledge of time sequence of localization of drugs in cells and tissues of animals may help in developing a better understanding of the actual overall pharmacokinetics of the drugs. We produced monoclonal antibody (mAb) against alogliptin (AG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, conjugated to BSA with N-(γ-maleimidobutyryloxy)-succinimide. The mAb was specific for AG and did not cross-react with sitagliptin, vancomycin or amoxicillin. The mAb enabled us to develop an immunohistochemical method for detecting the localization of AG in the rat small intestine. One hour after a single oral administration of AG, immunohistochemistry revealed that the immunoreactivity of AG was observed in almost all of cells and tissues of the duodenum. The microvilli of the absorptive epithelial cells were moderately stained. The staining pattern of AG at jejunum and ilium was almost the same as that of duodenum, but the staining intensity, especially at absorptive epithelial cells and intestinal gland epithelial cells, became stronger towards the distal part of the small intestine. These results suggested that AG may be more actively absorbed from the lower part of the small intestine than in the upper part. It may affect the function of cells with membrane-bound DPP-4 because it was reported that membrane-bound form of DPP-4 exists in the microvilli of the absorptive epithelial cells.
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Affiliation(s)
- Yuta Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Yutaro Yamamoto
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Tetsuya Saita
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
| | - Masashi Shin
- Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University
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Saad MA, Rastanawi AA, El-Yamany MF. Alogliptin abates memory injuries of hepatic encephalopathy induced by acute paracetamol intoxication via switching-off autophagy-related apoptosis. Life Sci 2018; 215:11-21. [DOI: 10.1016/j.lfs.2018.10.069] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/22/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023]
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Characterization of the post-prandial insulinemic response and low glycaemic index of a soy beverage. PLoS One 2017; 12:e0182762. [PMID: 28793331 PMCID: PMC5549974 DOI: 10.1371/journal.pone.0182762] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 07/24/2017] [Indexed: 02/07/2023] Open
Abstract
Soybean is recognized as rich source of bioactive compounds for the improvement of glucose homeostasis. However, the post-prandial mechanisms of action have not been extensively described. The aim of this study is to determine the changes in glucose homeostasis and related factors after acute intake of a soy beverage. Twenty-nine subjects (15 women and 14 men, with an average age of 19.5 ± 1.2) ingested 500 mL of water, glucose (20.5 g/500 mL) and soy beverage (20 g of carbohydrate) in three separate sessions. Capillary blood glucose was monitored every 15 min until 120 min post-prandial, and blood samples were collected at baseline and after 60 min for insulin, incretin, free amino acids, antioxidant capacity and inflammation marker analysis. The increase in capillary glucose after soy-beverage intake was negligible. This is explained in part by an increase in 83% in insulin levels than induced with glucose alone, which is mainly mediated by a low insulin degradation ratio (determined by c-peptide ratio), incretins and likely also by the modulation of the antioxidant environment. No associations were observed between the insulin levels and soy amino acid uptake. It could be concluded that the acute low glycaemic response of a soy beverage may involves a relationship between incretin and insulin secretion and insulin degradation.
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Gordillo Guerra P, Clerici P, Micouin L. Modular Access to N-Substituted cis 5-Amino-3-hydroxypiperidines. J Org Chem 2017; 82:7689-7694. [PMID: 28665596 DOI: 10.1021/acs.joc.7b01485] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A sequence of oxidative cleavage/reductive amination/reductive cleavage enables the preparation of N-substituted cis 5-amino-3-hydroxypiperidines from a readily available bicyclic adduct. This new route provides straightforward and versatile access to drug-relevant scaffolds or fragments.
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Affiliation(s)
- Paola Gordillo Guerra
- Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Faculté des Sciences Fondamentales et Bio-médicales, UMR 8601, CNRS-Paris Descartes University , 45 rue des Saints Pères, 75006 Paris, France
| | - Paolo Clerici
- Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Faculté des Sciences Fondamentales et Bio-médicales, UMR 8601, CNRS-Paris Descartes University , 45 rue des Saints Pères, 75006 Paris, France
| | - Laurent Micouin
- Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Faculté des Sciences Fondamentales et Bio-médicales, UMR 8601, CNRS-Paris Descartes University , 45 rue des Saints Pères, 75006 Paris, France
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26
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Abdel-Ghany MF, Ayad MF, Tadros MM. Enhanced LC-MS/MS analysis of alogliptin and pioglitazone in human plasma: Applied to a preliminary pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1058:93-101. [PMID: 28528664 DOI: 10.1016/j.jchromb.2017.04.043] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 04/07/2017] [Accepted: 04/25/2017] [Indexed: 10/19/2022]
Abstract
A new fast LC-MS/MS method was developed for determination of alogliptin and pioglitazone in human plasma. Linearity ranges of 10-400ngmL-1 for alogliptin and 25-2000ngmL-1 for pioglitazone, were found to be suitable for their bioanalysis covering the Cmin and Cmax values of the drugs. Direct precipitation technique was used for simultaneous extraction of the drugs successfully from human plasma samples. Chromatographic separation was achieved on a BEH C18 column (50mm×2.1mm, 1.7μm) with 0.1% aqueous formic acid: acetonitrile (40:60, v/v) at a flow rate of 0.3mLmin-1. The validated method was applied to a preliminary pharmacokinetic study on human volunteers. Monitoring the transition pairs of m/z 340.18 to 116.08 for alogliptin and m/z 356.99 to 133.92 for pioglitazone, using triple quadrupole mass spectrometer with multiple reaction monitoring, was achieved in the positive mode. The validated method is accurate and suitable for further clinical applications and possible bioequivalence studies.
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Affiliation(s)
- Maha F Abdel-Ghany
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt
| | - Miriam F Ayad
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt
| | - Mariam M Tadros
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
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Enhanced LC-MS/MS determination of alogliptin and metformin in plasma: Application to a pharmacokinetic study. Microchem J 2017. [DOI: 10.1016/j.microc.2016.10.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Takayanagi R, Uchida T, Kimura K, Yamada Y. Evaluation of drug efficacy of DPP-4 inhibitors based on theoretical analysis with pharmacokinetics and pharmacodynamics. Biopharm Drug Dispos 2016; 38:273-279. [PMID: 27976813 DOI: 10.1002/bdd.2057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 12/08/2016] [Accepted: 12/11/2016] [Indexed: 11/08/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for the treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, pharmacokinetic and pharmacodynamic parameters were used to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following the administration of four different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in the level of glucagon-like peptide-1 (GLP-1) induced by their administration. On the basis of the relationship shown, changes in clinical efficacy in association with dose change were examined in order to discuss clinical dosage from the standpoint of proper usage. The results indicate that a high rate of DPP-4 inhibition is necessary for the onset of the effect of an administered the DPP-4 inhibitor and that the average value for the DPP-4 inhibition rate can be utilized as a common parameter of clinical efficacy. Furthermore, the efficacy profiles of the present DPP-4 inhibitors could be demonstrated on the basis of an increase in the GLP-1 level. It is considered that the present findings provide useful information for promoting the proper clinical use of DPP-4 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Risa Takayanagi
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Takumi Uchida
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Koji Kimura
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Yasuhiko Yamada
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016. [PMID: 26218204 DOI: 10.1111/1440-1681.12469] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Yabe D, Seino Y. Alogliptin for the treatment of type 2 diabetes: a drug safety evaluation. Expert Opin Drug Saf 2016; 15:249-64. [PMID: 26607297 DOI: 10.1517/14740338.2016.1125467] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM. AREAS COVERED In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail. EXPERT OPINION Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer.
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Affiliation(s)
- Daisuke Yabe
- a Yutaka Seino Distinguished Center for Diabetes Research , Kansai Electric Power Medical Research Institute , Kobe , Japan.,b Center for Diabetes, Endocrinology and Metabolism , Kansai Electric Power Hospital , Osaka , Japan.,c Center for Clinical Nutrition and Metabolism , Kansai Electric Power Hospital , Osaka , Japan
| | - Yutaka Seino
- a Yutaka Seino Distinguished Center for Diabetes Research , Kansai Electric Power Medical Research Institute , Kobe , Japan.,b Center for Diabetes, Endocrinology and Metabolism , Kansai Electric Power Hospital , Osaka , Japan
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31
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Lu Y, Yang D, Li Z, Hang T, Song M. Isolation and characterization of related substances in alogliptin benzoate by LC-QTOF mass spectrometric techniques. J Pharm Biomed Anal 2016; 128:253-263. [PMID: 27281581 DOI: 10.1016/j.jpba.2016.04.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/15/2016] [Accepted: 04/19/2016] [Indexed: 11/19/2022]
Abstract
A highly specific and efficient LC-QTOF mass spectrometric method was developed for the separation and characterization of process related substances and the major degradation products in alogliptin benzoate and its tablets. The separation was performed on Phenomenex Gemini-NX C18 column (250mm×4.6mm, 5μm) using 0.2% formic acid-0.2% ammonium acetate in water as mobile phase A, acetonitrile and methanol (60:40, v/v) as mobile phase B in linear gradient elution mode. Forced degradation studies were also conducted under ICH prescribed stress conditions. Alogliptin benzoate and its tablets were tending to degrade under acid, alkaline, oxidative and thermal stresses, while relatively stable to photolytic stress. A total of seven related substances were detected and characterized through liquid chromatography-high resolution QTOF mass spectrometry techniques, including process related substances and degradation products, and two of them were further synthesized and characterized by NMR spectroscopy. Based on the related substances elucidation and the plausible formation mechanisms, efficient approaches were proposed to reduce or eliminate related substances, and in consequence the quality of alogliptin benzoate and its tablets have been promoted obviously. Therefore, the impurity profiles obtained are critical to the quality control and manufacturing processes optimization and monitoring of alogliptin benzoate and its tablets.
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Affiliation(s)
- Yuting Lu
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Danyi Yang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Zhiyu Li
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Taijun Hang
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
| | - Min Song
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
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32
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Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation. Sci Rep 2016; 6:29393. [PMID: 27381080 PMCID: PMC4933943 DOI: 10.1038/srep29393] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 06/16/2016] [Indexed: 12/13/2022] Open
Abstract
The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors.
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016; 42:999-1024. [PMID: 26173919 DOI: 10.1111/1440-1681.12455] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 06/11/2015] [Accepted: 07/06/2015] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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Liu D, Ma X, Liu Y, Zhou H, Shi C, Wu F, Jiang J, Hu P. Quantitative prediction of human pharmacokinetics and pharmacodynamics of imigliptin, a novel DPP-4 inhibitor, using allometric scaling, IVIVE and PK/PD modeling methods. Eur J Pharm Sci 2016; 89:73-82. [PMID: 27108678 DOI: 10.1016/j.ejps.2016.04.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 04/18/2016] [Accepted: 04/19/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE To predict the pharmacokinetic/pharmacodynamic (PK/PD) profiles of imigliptin, a novel DPP-4 inhibitor, in first-in-human (FIH) study based on the data from preclinical species. METHODS Imigliptin was intravenously and orally administered to rats, dogs, and monkeys to assess their PK/PD properties. DPP-4 activity was the PD biomarker. PK/PD profiles of sitagliptin and alogliptin in rats and humans were obtained and digitized from literatures. PK/PD profiles of all dose levels for each drug in each species were analyzed using modeling approach. Human CL, Vss and PK profiles of imigliptin were then predicted using Allometric Scaling (AS), in vitro in vivo extrapolation (IVIVE), and the steady-state plasma drug concentration - mean residence time (Css-MRT) methods. In vitro EC50 corrected by fu and in vivo EC50 in rats corrected by interspecies difference of sitagliptin and alogliptin were utilized separately to predict imigliptin human EC50. The prediction by integrating all above methods was evaluated by comparing observed and simulated PK/PD profiles in healthy subjects. RESULTS Full PK/PD profiles in animal were summarized for imigliptin, sitagliptin and alogliptin. Imigliptin CL, Vss, and Fa were predicted to be 19.1L/h, 247L, and 0.81 in humans, respectively. Predicted imigliptin AUCs, AUECs, and Emax in humans were within 0.8-1.2 times of observed values whereas other predicted PK/PD parameters were within 0.5-1.5 times of observed values. CONCLUSIONS By integrating available preclinical and clinical data, FIH PK/PD profiles of imigliptin could be accurately predicted.
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Affiliation(s)
- Dongyang Liu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Xifeng Ma
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Yang Liu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Huimin Zhou
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Chongtie Shi
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Frank Wu
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Ji Jiang
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Pei Hu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
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35
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Affiliation(s)
- Amar Puttanna
- Department of Diabetes and Endocrinology; City Hospital; Birmingham UK
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36
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Naik H, Czerniak R, Vakilynejad M. Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin. Br J Clin Pharmacol 2016; 81:700-12. [PMID: 26617339 DOI: 10.1111/bcp.12853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 11/13/2015] [Accepted: 11/26/2015] [Indexed: 02/04/2023] Open
Abstract
AIMS The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure. METHODS Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments. RESULTS A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively. CONCLUSIONS The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.
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Affiliation(s)
- Himanshu Naik
- Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA
| | - Richard Czerniak
- Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA
| | - Majid Vakilynejad
- Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL, 60015, USA
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Neumiller JJ, Holland DQ. Alogliptin + metformin combination for the treatment of type 2 diabetes mellitus. Expert Rev Endocrinol Metab 2016; 11:21-31. [PMID: 30063448 DOI: 10.1586/17446651.2016.1110484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The impact of type 2 diabetes mellitus continues to grow worldwide, with appropriate glycemic management being a cornerstone of treatment to minimize the risk of macrovascular and microvascular complications. While metformin is widely utilized as a first-line agent for patients without a contraindication to therapy, treatment guidelines recommend a variety of options for second-line dual therapy with patient-specific choices depending on assessment of hypoglycemia risk, weight effects, tolerability, cost and other considerations. Incretin-based therapies, inclusive of dipeptidyl peptidase-4 inhibitors, have become a widely utilized group of medications due to their potentially advantageous effects, such as a low risk of hypoglycemia and overall favorable tolerability profile. Accordingly, fixed-dose combination products containing metformin in combination with a dipeptidyl peptidase-4 inhibitor have been developed by several manufacturers. This article summarizes the current evidence for the safety and efficacy of alogliptin and metformin used in combination for the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Joshua J Neumiller
- a College of Pharmacy , Washington State University , Spokane , WA , USA
| | - Daniel Q Holland
- a College of Pharmacy , Washington State University , Spokane , WA , USA
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Lim SW, Jin JZ, Jin L, Jin J, Li C. Role of dipeptidyl peptidase-4 inhibitors in new-onset diabetes after transplantation. Korean J Intern Med 2015; 30:759-70. [PMID: 26552451 PMCID: PMC4642005 DOI: 10.3904/kjim.2015.30.6.759] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 10/14/2015] [Indexed: 02/06/2023] Open
Abstract
Despite strict pre- and post-transplantation screening, the incidence of new-onset diabetes after transplantation (NODAT) remains as high as 60%. This complication affects the risk of cardiovascular events and patient and graft survival rates. Thus, reducing the impact of NODAT could improve overall transplant success. The pathogenesis of NODAT is multifactorial, and both modifiable and nonmodifiable risk factors have been implicated. Monitoring and controlling the blood glucose profile, implementing multidisciplinary care, performing lifestyle modifications, using a modified immunosuppressive regimen, administering anti-metabolite agents, and taking a conventional antidiabetic approach may diminish the incidence of NODAT. In addition to these preventive strategies, inhibition of dipeptidyl peptidase-4 (DPP4) by the gliptin family of drugs has recently gained considerable interest as therapy for type 2 diabetes mellitus and NODAT. This review focuses on the role of DPP4 inhibitors and discusses recent literature regarding management of NODAT.
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Affiliation(s)
- Sun Woo Lim
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Zhe Jin
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
| | - Long Jin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jian Jin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
| | - Can Li
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
- Correspondence to Can Li, M.D. Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, #1327 JuZi St., Yanji 133000, China Tel: +86-433-266-0065 Fax: +86-433-251-3610 E-mail:
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Nakamura Y, Hasegawa H, Tsuji M, Udaka Y, Mihara M, Shimizu T, Inoue M, Goto Y, Gotoh H, Inagaki M, Oguchi K. Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors. World J Diabetes 2015; 6:840-9. [PMID: 26131325 PMCID: PMC4478579 DOI: 10.4239/wjd.v6.i6.840] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 03/16/2015] [Accepted: 04/01/2015] [Indexed: 02/05/2023] Open
Abstract
Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.
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Yamamoto T, Shimano M, Inden Y, Takefuji M, Yanagisawa S, Yoshida N, Tsuji Y, Hirai M, Murohara T. Alogliptin, a dipeptidyl peptidase-4 inhibitor, regulates the atrial arrhythmogenic substrate in rabbits. Heart Rhythm 2015; 12:1362-9. [DOI: 10.1016/j.hrthm.2015.03.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Indexed: 12/27/2022]
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Scheen AJ. Pharmacokinetics and clinical evaluation of the alogliptin plus pioglitazone combination for type 2 diabetes. Expert Opin Drug Metab Toxicol 2015; 11:1005-20. [PMID: 25936384 DOI: 10.1517/17425255.2015.1041499] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin). AREA COVERED An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy. EXPERT OPINION Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated.
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Affiliation(s)
- André J Scheen
- University of Liège, Center for Interdisciplinary Research on Medicines (CIRM), Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU Sart Tilman , Liège , Belgium +32 4 3667238 ; +32 4 3667068 ; andre.scheen@ chu.ulg.ac.be
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Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, augment glucose-dependent insulin secretion and suppress glucagon levels through enhancement of the action of endogenous incretin by inhibiting DPP-4, an incretin-degrading enzyme. DPP-4 inhibitors are generally well tolerated because of their low risk of hypoglycemia and other adverse events. Moreover, with their potential to improve beta cell function, a core defect of type 2 diabetes, DPP-4 inhibitors are becoming a major component of treatment of type 2 diabetes. Alogliptin benzoate is a newly developed, highly selective DPP-4 inhibitor which has been approved in many countries throughout the world. Once-daily administration of alogliptin as either monotherapy or combination therapy with other oral antidiabetic drugs or insulin has a potent glucose-lowering effect which is similar to that of other DPP-4 inhibitors, with a low risk of hypoglycemia and weight gain. The cardiovascular safety of this drug has been confirmed in a recent randomized controlled trial. This review summarizes the efficacy and safety of alogliptin, and discusses the role of DPP-4 inhibitors in the treatment of type 2 diabetes.
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Affiliation(s)
- Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Ceriello A, Sportiello L, Rafaniello C, Rossi F. DPP-4 inhibitors: pharmacological differences and their clinical implications. Expert Opin Drug Saf 2015; 13 Suppl 1:S57-68. [PMID: 25171159 DOI: 10.1517/14740338.2014.944862] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Recently, incretin-based therapy was introduced for the treatment of type 2 diabetes (T2D). In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) play an increasing role in the management of T2D. AREAS COVERED An extensive literature search was performed to analyze the pharmacological characteristics of DPP-4i and their clinical implications. EXPERT OPINION DPP-4i present significant pharmacokinetic differences. They also differ in chemical structure, in the interaction with distinct subsites of the enzyme and in different levels of selectivity and potency of enzyme inhibition. Moreover, disparities in the effects on glycated hemoglobin, glucagon-like peptide-1 and glucagon levels and on glucose variability have been observed. However, indirect comparisons indicate that all DPP-4i have a similar safety and efficacy profiles. DPP-4i are preferred in overweight/obese and elderly patients because of the advantages of minimal or no influence on weight gain and low risk of hypoglycemia. For the same reasons, DPP-4i can be safely combined with insulin. However, currently cardiovascular outcomes related to DPP-4i are widely debated and the available evidence is controversial. Today, long-term studies are still in progress and upcoming results will allow us to better define the strengths and limits of this therapeutic class.
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Affiliation(s)
- Antonio Ceriello
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Department of Endocrinology , Barcelona , Spain
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Abstract
INTRODUCTION Type 2 diabetes mellitus continues to be a global problem, placing an enormous burden on healthcare systems and resources. Effective treatment options to minimize the effects of hyperglycemia are essential. Most patients eventually need to take multiple drugs to maintain glycemic control, and many antidiabetic drugs are associated with adverse effects, such as hypoglycemia, weight gain or gastrointestinal effects. Dipeptidyl peptidase (DPP)-4 inhibitor is one of the newer classes of oral antidiabetic drug, and alogliptin is the most recently approved drug in this class. AREAS COVERED This paper reviews the pharmacodynamic and pharmacokinetic properties of alogliptin and the results of clinical trials evaluating its efficacy at improving glycemic control in patients with type 2 diabetes both as monotherapy and in combination with other antidiabetic drugs. The drug's tolerability and safety profiles are also considered. EXPERT OPINION Alogliptin is a DPP-4 inhibitor that can help in improving glycemic control in patients with type 2 diabetes, including the elderly. It is generally well tolerated and does not increase the risk of hypoglycemia or weight gain.
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Affiliation(s)
- Yutaka Seino
- Kansai Electric Power Hospital, Center for Diabetes, Endocrinology and Metabolism, , 1-7, Fukushima 2-chome, Fukushima-ku, Osaka, 553-0003 , Japan +81 6 6458 5821 ; +81 6 7501 1403 ;
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Ioannidis I. Diabetes treatment in patients with renal disease: Is the landscape clear enough? World J Diabetes 2014; 5:651-658. [PMID: 25317242 PMCID: PMC4138588 DOI: 10.4239/wjd.v5.i5.651] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 03/31/2014] [Accepted: 07/18/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes is the most important risk factors for chronic kidney disease (CKD). The risk of CKD attributable to diabetes continues to rise worldwide. Diabetic patients with CKD need complicated treatment for their metabolic disorders as well as for related comorbidities. They have to treat, often intensively, hypertension, dyslipidaemia, bone disease, anaemia, and frequently established cardiovascular disease. The treatment of hypoglycaemia in diabetic persons with CKD must tie their individual goals of glycaemia (usually less tight glycaemic control) and knowledge on the pharmacokinetics and pharmacodynamics of drugs available to a person with kidney disease. The problem is complicated from the fact that in many efficacy studies patients with CKD are excluded so data of safety and efficacy for these patients are missing. This results in fear of use by lack of evidence. Metformin is globally accepted as the first choice in practically all therapeutic algorithms for diabetic subjects. The advantages of metformin are low risk of hypoglycaemia, modest weight loss, effectiveness and low cost. Data of UKPDS indicate that treatment based on metformin results in less total as well cardiovascular mortality. Metformin remains the drug of choice for patients with diabetes and CKD provided that their estimate Glomerular Filtration Rate (eGFR) remains above 30 mL/min per square meter. For diabetic patients with eGFR between 30-60 mL/min per square meter more frequent monitoring of renal function and dose reduction of metformin is needed. The use of sulfonylureas, glinides and insulin carry a higher risk of hypoglycemia in these patients and must be very careful. Lower doses and slower titration of the dose is needed. Is better to avoid sulfonylureas with active hepatic metabolites, which are renally excreted. Very useful drugs for this group of patients emerge dipeptidyl peptidase 4 inhibitors. These drugs do not cause hypoglycemia and most of them (linagliptin is an exception) require dose reduction in various stages of renal disease.
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Davis TME. Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes Metab 2014; 16:891-9. [PMID: 24684351 DOI: 10.1111/dom.12295] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/19/2014] [Accepted: 03/25/2014] [Indexed: 01/18/2023]
Abstract
The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.
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Affiliation(s)
- T M E Davis
- School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, Australia
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Dejager S, Schweizer A. Incretin therapies in the management of patients with type 2 diabetes mellitus and renal impairment. Hosp Pract (1995) 2014; 40:7-21. [PMID: 22615074 DOI: 10.3810/hp.2012.04.965] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and clinical positioning of these agents in RI populations.
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Ndefo UA, Okoli O, Erowele G. Alogliptin: A new dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. Am J Health Syst Pharm 2014; 71:103-9. [PMID: 24375601 DOI: 10.2146/ajhp130131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
PURPOSE The pharmacology, pharmacodynamics, pharmacokinetics, safety, efficacy, and place in therapy of alogliptin and its combinations for managing type 2 diabetes mellitus are reviewed. SUMMARY Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). It works by slowing the inactivation of the incretin hormones, thereby increasing their concentrations in the bloodstream and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin has a moderate degree of absorption, estimated to exceed 75%, and its absorption is not affected by food. No drug interactions are known to be associated with alogliptin monotherapy. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The clinical efficacy and safety of alogliptin have been demonstrated in several clinical trials, reducing patients' glycosylated hemoglobin level by 0.4-1.0% in 26 weeks. Alogliptin does not require any dosage adjustment when coadministered with ketoconazole, fluconazole, gemfibrozil, warfarin, metformin, glyburide, and pioglitazone. Alogliptin selectively binds to and inhibits DPP-4 in vitro at concentrations approximating therapeutic exposures. The most common adverse events associated with alogliptin are nasopharyngitis, headache, and upper respiratory tract infection. As with the other DPP-4 inhibitors, use of alogliptin may be associated with the development of pancreatitis during therapy. CONCLUSION Alogliptin, a selective DPP-4 inhibitor, does not differ greatly from the other DPP-4 inhibitors currently available. It can be used as monotherapy or in combination with metformin for the management of type 2 diabetes.
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Affiliation(s)
- Uche Anadu Ndefo
- Uche Anadu Ndefo, Pharm.D., BCPS, is Assistant Professor, Department of Pharmacy Practice, Texas Southern University, Houston. Okwuchukwu Okoli, M.D., is Field Physician, Doctors Without Borders/Medecins Sans Frontieres, New York, NY. Goldina Erowele, Pharm.D., is Clinical Pharmacist III, Department of Pharmacy, Harris Health Systems, Houston
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Giorda CB, Nada E, Tartaglino B. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine 2014; 46:406-19. [PMID: 24510630 DOI: 10.1007/s12020-014-0179-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 01/16/2014] [Indexed: 12/14/2022]
Abstract
Renal or hepatic impairment, often encountered in patients with type 2 diabetes, influences the pharmacokinetics and bioavailability of antihyperglycemic agents. An emerging concern is whether pharmacotherapy with incretin-based agents, the most recent drug classes to be introduced for type 2 diabetes, can be safely used in patients with renal insufficiency or hepatic damage. This literature review examines the results of studies on these novel drug classes, with a view to provide the practitioner with a balanced, evidence-based position when considering incretin-based therapies in patients with type 2 diabetes and impaired kidney or liver function. All currently available dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be appropriate pharmacotherapeutic choices in patients with declining renal function, with linagliptin affording the added advantage of not requiring dose adjustment or periodic monitoring of drug-related kidney function. In contrast, caution is warranted with the use of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with moderate or severe renal impairment. The slightly wider evidence base for liraglutide than for exenatide or lixisenatide is not sufficient to support its use in severe renal impairment. What little evidence there is for incretin-based therapies in hepatic impairment has come from a few past hoc analysis of clinical trials, with most precautions and warnings reflecting the paucity of knowledge about incretin efficacy or safety in this condition.
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Affiliation(s)
- Carlo B Giorda
- Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy,
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