Pharmacokinetic, pharmacodynamic and clinical evaluation of saxagliptin in type 2 diabetes

Anderson, Rose G.; Hayes, Jennifer; Stephens, Jeffrey W.

doi:10.1517/17425255.2016.1154044

Cited by 12 publications

(9 citation statements)

References 47 publications

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“…These findings have resulted in eight commercially available DPP-IV inhibitors, including alogliptin (Nesina ® , Vipidia ® ; Keating, 2015;Takeda et al, 2016), anagliptin , gemigliptin (Zemiglo ® ; Kim et al, 2013;Jung et al, 2014), linagliptin (Forst and Pfutzner, 2012;Barnett, 2015), saxagliptin Anderson et al, 2016), sitagliptin (Januvia ® , Xelevia ® , Glactiv ® , Tesavel ® ; Garg et al, 2013;Plosker, 2014), teneligliptin (Nakamaru et al, 2015), and vildagliptin (Galvus ® , Novartis AG; Mikhail, 2008;Richter et al, 2008), being approved and entering into the clinic . These DPP-IV inhibitors have good oral bioavailability and a relatively long duration of action in patients with T2DM.…”

Section: Dpp-iv Inhibitor and T2dmmentioning

confidence: 99%

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Hölscher

2016

Reviews in the Neurosciences

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AbstractIncretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

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Section: Dpp-iv Inhibitor and T2dmmentioning

confidence: 99%

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Hölscher

2016

Reviews in the Neurosciences

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“…Several reviews comparing saxagliptin and/or other marketed DPP-4 inhibitors are available in the literature [19][20][21][22][23]. This review focuses on the clinical pharmacological characteristics of saxagliptin.…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor

Boulton

2016

Clin Pharmacokinet

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Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration-time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug-drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.

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“…Other DPP-4 inhibitors have shown 2-to 6-fold increases in the plasma GLP-1 levels in patients with T2DM. 17,[24][25][26][27] Thus, the present study showed that fotagliptin can increase active GLP-1 levels in patients with T2DM more efficaciously than other reported DPP-4 inhibitors. This study supports a once-daily treatment of fotagliptin in patients with T2DM.…”

Section: Discussionmentioning

confidence: 78%

Safety, Pharmacokinetics, and Pharmacodynamics of a Dipeptidyl Peptidase‐4 Inhibitor: A Randomized, Double‐Blinded, Placebo‐Controlled Daily Administration of Fotagliptin Benzoate for 14 Days for Type 2 Diabetes Mellitus

Zhang

et al. 2021

Clinical Pharm in Drug Dev

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This study investigated the pharmacokinetics, pharmacodynamics, and safety of fotagliptin benzoate (fotagliptin), a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Chinese patients with type 2 diabetes mellitus (T2DM). In a randomized, doubleblinded, placebo-controlled study, 10 and 4 patients with T2DM were randomized and received, respectively, once-daily oral fotagliptin (24 mg) or placebo, for 14 days. The pharmacokinetics and pharmacodynamics were assessed throughout the study, including monitoring DPP-4, glucagon-like peptide-1 (GLP-1), glycosylated hemoglobin, and fasting blood glucose. Fotagliptin was rapidly absorbed, and the median time to maximum concentration value was ∼1.5 hours. Plasma fotagliptin levels were stable after 14 days of once-daily dosage. The accumulation ratios for the area under the plasma concentration-time curve of fotagliptin, M1, and M2-1, were 1.19 ± 0.10, 1.59 ± 0.27, and 1.39 ± 0.26, respectively. The durations for DPP-4 inhibition >80% in the fotagliptin group on days 1 and 14 were 23.5 and 24.0 hours, respectively. The concentrations of GLP-1 were higher on days 1 and 14 than at the baseline. No serious complications occurred. Fotagliptin showed favorable pharmacokinetics and pharmacodynamics and was well tolerated. Treatment with fotagliptin can achieve high DPP-4 inhibition and increase plasma GLP-1. A once-per-day dosing regimen may be recommended as clinically efficacious.

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Pharmacokinetic, pharmacodynamic and clinical evaluation of saxagliptin in type 2 diabetes

Cited by 12 publications

References 47 publications

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor

Safety, Pharmacokinetics, and Pharmacodynamics of a Dipeptidyl Peptidase‐4 Inhibitor: A Randomized, Double‐Blinded, Placebo‐Controlled Daily Administration of Fotagliptin Benzoate for 14 Days for Type 2 Diabetes Mellitus

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