Alogliptin

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Alogliptin
Systematic (IUPAC) name
2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
Clinical data
Trade namesNesina
Kazano (with metformin)
Oseni (with pioglitazone)
Pregnancy cat.B (US)
Legal status Prescription only
RoutesOral
Pharmacokinetic data
Bioavailability100%
Protein binding20%
MetabolismLimited, hepatic (CYP2D6- and 3A4-mediated)
Half-life12–21 hours
ExcretionRenal (major) and fecal (minor)
Identifiers
CAS number850649-62-6 YesY
ATC codeA10BH04
PubChemCID 11450633
ChemSpider9625485 YesY
UNIIJHC049LO86 YesY
KEGGD06553 YesY
ChEBICHEBI:72323 N
ChEMBLCHEMBL376359 YesY
Chemical data
FormulaC18H21N5O2 
Mol. mass339.39 g/mol
 N (what is this?)  (verify)
 
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Alogliptin
Systematic (IUPAC) name
2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
Clinical data
Trade namesNesina
Kazano (with metformin)
Oseni (with pioglitazone)
Pregnancy cat.B (US)
Legal status Prescription only
RoutesOral
Pharmacokinetic data
Bioavailability100%
Protein binding20%
MetabolismLimited, hepatic (CYP2D6- and 3A4-mediated)
Half-life12–21 hours
ExcretionRenal (major) and fecal (minor)
Identifiers
CAS number850649-62-6 YesY
ATC codeA10BH04
PubChemCID 11450633
ChemSpider9625485 YesY
UNIIJHC049LO86 YesY
KEGGD06553 YesY
ChEBICHEBI:72323 N
ChEMBLCHEMBL376359 YesY
Chemical data
FormulaC18H21N5O2 
Mol. mass339.39 g/mol
 N (what is this?)  (verify)

Alogliptin (codenamed SYR-322, trade name Nesina)[1] is an orally administered anti-diabetic drug in the DPP-4 inhibitor class,[2] developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005.

Clinical study[edit]

A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and voglibose among newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors.[3]

A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was "non-inferior" to a "very low fat/calorie traditional Japanese diet" among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI.[4]

A randomized clinical trial reporting in 2011 aimed to demonstrate the efficacy of alogliptin as an add-on agent in combination with metformin and pioglitazone versus simply increasing the dosage of pioglitazone in combination with metformin; in other words, this was a study to look at a three-agent therapy versus a two-agent therapy. The outcome of this study suggested that the addition of alogliptin to metformin and pioglitazone provided superior impact on diabetes biomarkers (e.g. HbA1c) than increasing the dose of pioglitazone in a two agent therapy with metformin.[5]

Reported adverse events[edit]

Adverse events appear to be restricted to mild hypoglycemia based on clinical studies.[3][4][5]

Market access[edit]

In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Adminiistration (USFDA),[6] after positive results from Phase III clinical trials.[1] In September of 2008, the company also filed for approval in Japan,[7] winning approval in April 2010.[6] The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data.[7] The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011.[6] In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.[6]

In 2013 the FDA approved the drug in three formulations: As a stand-alone with the brand-name Nesina. Combined with metformin using the name Kazano, and when combined with pioglitazone as Oseni.

References[edit]

  1. ^ a b "Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S." (Press release). Takeda Pharmaceutical Company. January 4, 2008. Retrieved January 9, 2008. 
  2. ^ Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. (2007). "Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV". J. Med. Chem. 50 (10): 2297–2300. doi:10.1021/jm070104l. PMID 17441705. 
  3. ^ a b Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei (September 2011), "Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only)", Current Medical Research and Opinion 27 (9): 1781–1792, doi:10.1185/03007995.2011.599371, PMID 21806314, retrieved April 26, 2012 
  4. ^ a b Kutoh, Eiji; Ukai, Yasuhiro (2012), "Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only)", Endocrine (January 17, 2012), doi:10.1007/s12020-012-9596-0, PMID 22249941, retrieved April 26, 2012 
  5. ^ a b Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R. (October 2011), "Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study", Diabetes, Obesity and Metabolism (October 27, 2011) 13 (12): 1088–1096, doi:10.1111/j.1463-1326.2011.01463.x, retrieved April 26, 2012 
  6. ^ a b c d Grogan, Kevin (April 26, 2012), "FDA wants yet more data on Takeda diabetes drug alogliptin", PharmaTimes (PharmaTimes), PharmaTimes online, retrieved April 26, 2012 
  7. ^ a b "GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy". Genetic Engineering & Biotechnology News. June 4, 2009.