Vildagliptin

Vildagliptin was approved by the European Medicines Agency (EMA) on Sep 26, 2007, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jan 20, 2010, following by China Food and Drug Administration (CFDA) on Aug 15, 2011. It was developed and marketed as Galvus® by Novartis in EU.

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet α-cell and β-cell responsiveness to glucose. It is used to reduce hyperglycemia in type 2 diabete.

Galvus®is available as film-coated tablet for oral use, containing 50 mg free Vildagliptin. The recommended dose of vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.

Index：

General Information

Update Date：2016-03-08

Drug Name：
Vildagliptin
Research Code：
LAF-237; DSP-7238; NVP-LAF-237
Trade Name：
Galvus® / Jalra® / Xiliarx® / Equa®
MOA：
Dipeptidyl peptidase-4 (DPP-4) inhibitor
Indication：
Type 2 diabetes
Status：
Approved
Company：
Novartis (Originator)
Sales：
$1,140 Million (Y2015);
$1,224 Million (Y2014);
$1,200 Million (Y2013);
$910 Million (Y2012);
$677 Million (Y2011);
ATC Code：
A10BH02
Approved Countries or Area

Update Date：2015-07-29

Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2008-11-19 Marketing approval Xiliarx Type 2 diabetes Tablet 50 mg Novartis
2008-11-19 Marketing approval Jalra Type 2 diabetes Tablet 50 mg Novartis
2007-09-26 Marketing approval Galvus Type 2 diabetes Tablet, Film coated 50 mg Novartis
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Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2010-01-20 Marketing approval Equa Type 2 diabetes Tablet 50 mg Novartis
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Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2011-08-15 Marketing approval 佳维乐/Galvus Type 2 diabetes Tablet 50 mg Novartis
2011-08-15 Marketing approval 佳维乐/Galvus Type 2 diabetes Tablet 50 mg Novartis
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Chemical Structure

Update Date：2015-09-17

Molecular Weight 303.4
Formula C17H25N3O2
CAS No. 274901-16-5 (Vildagliptin);
Chemical Name (2S)-1-{2-[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile
Vildagliptin （Free Acid/Base）Parameters：
MW HD HA FRB* PSA* cLogP*
303.4 2 5 4 76.4 0.169±0.567
*：Calculated by ACD/Labs software V11.02.
Related Patents

Update Date：2015-11-17

No. Major Technical Classification Publication No. Patent No. Legal Status Filling Date Estimated Expiry Date
1 Combination CN1977842A Refusal 2001/1/19
2 Uses CN1921856A Refusal 2005/2/18
3 Uses CN1905876A CN1905876B Granted 2004/11/16 2024/11/16
4 Combination CN1901938A Withdrawn 2004/11/16
5 Preparation CN1774420A CN1774420B Granted 2004/4/15 2024/4/15
6 Formulation CN1720042A CN100348189C Granted/abandoned 2003/12/9 2010/12/9
7 Uses CN1658867A CN100402026C Granted/abandoned 2003/6/2 2015/6/2
8 Combination CN1655786A Refusal 2003/5/28
9 Combination CN1642559A Refusal 2003/3/21
10 Others CN1604968A Withdrawn 2002/10/30
11 Combination CN1400908A Refusal 2001/1/19
12 Formula CN1329593A CN1160330C Granted 1999/12/9 2019/12/9
13 Others CN104080471A Examination 2012/10/12
14 Combination CN102327614A Examination 2001/1/19
15 Formula CN101918423A CN101918423B Granted 2008/11/25 2028/11/25
16 Others CN101677970A Withdrawn 2008/5/12
17 Formulation CN101618216A CN101618216B Granted 2005/1/17 2025/1/17
18 Formula CN101610761A Withdrawn 2007/12/20
19 Uses CN101557811A Withdrawn 2007/10/30
20 Combination CN101537182A Withdrawn 2003/3/21
21 Combination CN101518650A Withdrawn 2003/5/28
22 Formula CN101472892A Withdrawn 2007/4/10
23 Formula CN101410397A Withdrawn 2007/3/29
24 Uses CN101394848A Withdrawn 2007/1/4
25 Formula CN101384594A Withdrawn 2006/12/20
26 Formulation CN101287495A Withdrawn 2006/6/8
27 Formulation CN101277688A CN101277688B Granted 2006/9/25 2026/9/25
28 Uses CN101273987A Withdrawn 2003/6/2
29 Combination CN101272780A Withdrawn 2006/9/28
30 Uses CN101267838A CN101267838B Granted 2006/9/18 2026/9/18
31 Formulation CN101262851A Refusal 2005/1/17
32 Salt CN101238099A Withdrawn 2006/8/2
33 Formulation CN101222919A Withdrawn 2006/7/11
34 Formulation CN101208085A CN101208085B Granted 2006/6/8 2026/2/8
35 Formulation CN101106977A Withdrawn 2006/1/17
36 Preparation CN101037409A CN101037409B Granted 2004/4/15 2024/4/15
37 Formulation CN101035536A Withdrawn 2005/10/6
38 Combination CN101035522A CN101035522B Granted/abandoned 2005/10/21 2012/10/21
39 Combination CN101018550A Withdrawn 2005/7/13
40 Formulation CN101010068A CN101010068B Granted 2005/8/26 2025/8/26
More
Synthesis & Impurities

Update Date：2015-10-09


1. WO2004092127A1.

2. WO0034241A1.

3. J. Med. Chem. 2003, 46, 2774-2789.

4. WO2010022690A2.

5. WO2011012322A2.

6. WO2011101861A1.


1. Beilstein J. Org. Chem. 2008, 4, 20.


1. WO2011101861A1.


1. WO2011101861A1.


1. WO2011101861A1.


1. WO2012004210A1.

1
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity A C17H25N3O2 303.4 1789703-37-2
2
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity B C17H27N3O3 321.41 565453-39-6
3
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity C C17H24N2O3 304.38 1789703-36-1
4
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity D C17H25N3O2 303.4 1036959-27-9
5
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity E C17H26N2O4 322.4 565453-41-0
6
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity F C24H33N5O3 439.55 1036959-23-5
7
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity G C17H25D3N3O2 306.4 1217546-82-1
8
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Vildagliptin impurity H C17H25D6N3O2 309.4
Non-clinical Pharmacology

Update Date：2016-06-15

Mechanism of Action

●    Vildagliptin treated diabetes by:

v    DPP-4 inhibition (main action);

v    Prolong GLP-1 and GIP life time;

v    Promote insulin production and secretion;

v    Reduce blood glucose concentration.

●   DPP-4 inhibition efficacy by vildagliptin:

v   DPP-4 from human plasma IC50=2.7 nM.

v   Selectivities to DPP-2>10000, DPP-8=253, DPP-9=32.5, FAPα=49501,2

●   Vildagliptin was indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus3,4,5,6,7,8

[1].    Japan, PMDA.

[2].   Drug@EMA, EMEA/H/C/000771 Galvus : EPAR - Scientific Discussion.

[3].   Postgrad. Med. J. 2008, 84, 524-531.

[4].   Diabetes Obes. Metab. 2011, 13, 7-18.

[5].   Diabetes Metab. 2012, 38, 89-101.

[6].   Formulary 2008, 43, 122-124, 131-134.

[7].   Br. J. Diabetes Vasc. Dis. 2008, 8, S10-S18.

[8].   Drugs 2011, 71, 1441-1467.

[9].   The relevance of off-target polypharmacology; John Wiley & Sons, Inc., 2012.

[10].   Int. J. Clin. Pract. Suppl. 2008, 62, 8-14.

[11].   Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 479-486.

In Vivo Efficacy

●    Vildagliptin significantly inhibited DPP-4 activity at 0.3 mg/kg.

●    Vildagliptin significantly increased GLP-1 concentration at 0.3 mg/kg.

●    Vildagliptin significantly decreased glucose concentration at 0.3 mg/kg.

●    Vildagliptin significantly delayed gastric empty at 0.3 mg/kg.

●    Vildagliptin significantly could protect pancreatic β cell at 60 mg/kg.

[1].    Japan, PMDA.

[2].   Drug@EMA, EMEA/H/C/000771 Galvus : EPAR - Scientific Discussion.

[3].   Postgrad. Med. J. 2008, 84, 524-531.

[4].   Diabetes Obes. Metab. 2011, 13, 7-18.

[5].   Diabetes Metab. 2012, 38, 89-101.

[6].   Formulary 2008, 43, 122-124, 131-134.

[7].   Br. J. Diabetes Vasc. Dis. 2008, 8, S10-S18.

[8].   Drugs 2011, 71, 1441-1467.

[9].   The relevance of off-target polypharmacology; John Wiley & Sons, Inc., 2012.

[10].   Int. J. Clin. Pract. Suppl. 2008, 62, 8-14.

[11].   Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 479-486.

Non-clinical Pharmacokinetics

Update Date：2016-06-15

Absorption

●    Vildagliptin had high oral bioavailability in dogs (100%), monkeys (92%) and humans (85%) but only moderate bioavailability in rats (45%).

●    Vildagliptin was rapidly absorbed, with Tmax occurring 0.5 to 1.5 hrs post-dose in non-clinical species and humans.

●    A half-life in monkeys (9.2 hrs) was longer than in mice, rats, dogs or humans (0.97-5.5 hrs).

●    The Vdss in rats (8.5 L/kg) was higher than in mice (2.3L/kg), dogs (1.6L/kg), monkeys (2.6L/kg) and humans (0.9 L/kg).

●    Vildagliptin had a moderate permeability with Papp (A-B) =1.5×10-6 cm/s in Caco-2 cell model.

[1]. Japan, PMDA.

Distribution

●    Vildagliptin showed low binding to plasma proteins in all species (<10%), main metabolite LAY105 showed no binding to plasma proteins in humans.

●    In a whole body autoradiography study in rats:

v    Vildagliptin-related radioactivity was rapidly distributed to most tissues. Drug-related radioactivity was bound to melanin.

v    There was a low passage for drug-related radioactivity across the blood-brain barrier.

v    Bioradioactivity was not detected in any tissue at 48 hrs postdose.

[1]. Japan, PMDA.

Metabolite

●    The metabolism of vildagliptin was low in liver slices and human liver microsomes, clearance in human kidney and intestinal microsomes was higher than in liver microsmes.

●    The parent compound was one of the major circulating components in all species and all metabolites observed in humans were also found in the animal species.

v    In humans, the predominant metabolic pathway was hydrolysis at cyano moiety to form a carboxylic acid metabolite (M20.7/LAT151), accounting for approximately 55% of circulating drug-related materials following an oral dose.

v    M20.7 was the main metabolite both in rats (54%) and dogs (33%) following an oral administration.

v    In the rabbits, another hydrolysis product M15.3 was the main metabolite (53%) following an oral dose.

●    Hydrolysis was the main mechanism of vildagliptin metabolism in all species and exposure to the major metabolites was broadly similar in rats, dogs and humans.

●    The DPP inhibitory activity of M20.7 was very weak and the M15.3 had no DPP inhibitory activity.

[1]. Japan, PMDA.

Excretion

●    Urinary excretion was the main route in all species except rats, the major component in urine was LBQ770/M15.3 (rabbit), the major components in urine and feces were LAY151/M20.7 (dog and human), BQS867/M20.2 (monkey).

●    In rats, equal amounts were excreted through urine (LAY151) and feces (parent).

 

[1]. Japan, PMDA.

Drug-Drug Interaction

●    Vildagliptin was not the inducer of CYP1A2, 2C8, 2B6, 2C9, 2C19, 3A or P-gp, MRP2.

●    Vildagliptin and metabolite LAY151 were not the inhibitors of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4/5.

●    Vildagliptin was a substrate of P-gp, but LAY151 was not a substrate of P-gp or MRP2.

●    Vildagliptin and LAY151 were not inhibitors of P-gp, BCRP, hOAT3, hOAT1, hOCT1, MRP2 or MRP4.

[1]. Japan, PMDA.

Non-clinical Toxicology

Update Date：2016-06-15

Single Dose Toxicity

●    Vildagliptin exhibited low acute toxicity.

●    In mice and rats no toxicological signs were observed after a single oral dose of 2000 mg/kg:

v    Mice MTD: 2000 mg/kg.

v    Rats MTD: 2000 mg/kg.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation

Repeated Dose Toxicity

●    Repeated dose toxicity studies were performed in rats (up to 26 weeks) and dogs (up to 52 weeks), mice and monkeys (up to 13 weeks).

●    For mice, NOAEL was 250 mg/kg/day, 43×MRHD, the main toxicological effect was the accumulation of clusters of foamy alveolar macrophages in the lung.

●    For rats, NOAEL was 25 mg/kg/day, 6×MRHD, the main toxicological effect was the accumulation of clusters of foamy alveolar macrophages in the lung.

●    For dogs, NOAEL was about 5 mg/kg/day, 2.5×MRHD, the most consistent toxicological finding was the appearance of gastrointestinal symptoms, particularly soft feces, mucoid feces, diarrhea and at higher doses, faecal blood.

●    For monkeys, NOAEL was about 3 mg/kg/day, 0.4×MRHD, the major toxicological effect was skin lesion.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation

Safety Pharmacology

●    No effects on central nervous system.

●    In vitro hERG channel: vildagliptin and its major metabolites had no effects.

●    In vitro IC50 for sodium channels of vildagliptin: 365.8 µM (475×MRHD).

●    Cardiovascular changes were observed in dogs at high doses, occasionally resulting in mortality, based on dog exposure data (Cmax≥52×MRHD), a clinical effect was unlikely.

●    For monkeys, transient blood pressure and heart rate increased at 40 mg/kg/day (≥16×MRHD).

●    No effects on T-cell activation or PBMC or bone marrow cells proliferation up to 10 µM.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation

Genotoxicity

●    No genotoxicity risk was found.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation

Reproductive and Developmental Toxicity

●    Fertility toxicity in rats: NOAEL was 900 mg/kg/day for males and females.

●    Embryo-fetal toxicity: NOAEL was 750 mg/kg/day and 50 mg/kg/day for rats and rabbits respectively.

●    In the pre- and postnatal toxicity study in rats: NOAEL was 25 mg/kg/day for offspring (F1).

●    Studies in pregnant rats and rabbits demonstrated placental transfer of vildagliptin.

●    Milk transfer of vildagliptin and metabolites were demonstrated in the rat, with a milk/plasma ratio for total radioactivity of 4.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation

Carcinogenicity

●    For mice, NOAELs were 100 and 500 mg/kg/day, 21× and 79×MRHD for male and female respectively, there was an increased incidence of hemangiosarcomas and mammary carcinoma.

●    For rats, NOAELs were 900 mg/kg/day, 287× and 247×MRHD for male and female respectively, no evidence for a carcinogenic potential was observed in rats.

[1]. Japan, PMDA.

[13]. Drug@EMA, EMEA/H/C/000771 Galvus-H-C-771-WS-257 : EPAR - Assessment Report - Variation