Vildagliptin
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| Non-proprietary name | Vildagliptin | |||||||||||||||||||||
| other names |
(2 S ) - {[(3-Hydroxyadamantan-1-yl) amino] acetyl} pyrrolidine-2-carbonitrile ( IUPAC ) |
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| Molecular formula | C 17 H 25 N 3 O 2 | |||||||||||||||||||||
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| Molar mass | 303.40 g mol −1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
148-150 ° C |
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very good in water and DMSO |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Vildagliptin is an anti- diabetic drug .
The adamantane derivative vildagliptin is to Sitagliptin the second drug from the new class of dipeptidyl peptidase-4 inhibitors as Villhauer named and was after its discoverer, the chemist Edwin. In contrast to incretin mimetics such as exenatid , these gliptins do not imitate the structure of incretins, but hinder their breakdown. Like all newly approved drugs, vildagliptin requires a prescription .
Approval and Marketing
After Europe-wide approval by the European Commission, the drug was launched on the market by Novartis in spring 2008 under the name Galvus for the oral treatment of type 2 diabetes mellitus in adults. This was followed by a fixed combination with metformin under the name Eucreas (international Galvus-Met ).
In Germany, the Federal Joint Committee (G-BA) found in its resolution of October 1, 2013 that vildagliptin had no additional benefit compared to the comparator therapy with a sulfonylurea. As a result, the manufacturer should have entered into negotiations with the health insurers about the reimbursement price. Instead, Novartis decided to discontinue sales in Germany on July 1, 2014, as "no agreement could be reached with the National Association of Statutory Health Insurance Funds [...] regarding a reasonable price". In October 2018, Galvus and Eucreas came back onto the market in Germany.
Mode of action and pharmacology
Incretins
The glucose-dependent insulinotropic peptide ( GIP ) and the glucagon-like peptide 1 ( GLP-1 ) are incretins that are continuously secreted by the intestine into the bloodstream . The incretin release is increased after a meal. Both GIP and GLP-1 increase the synthesis and release of insulin from the β-cells of the islets of Langerhans , which in turn are located in the pancreas . GLP-1 also lowers glucagon excretion, the main task of which is to increase blood sugar levels and which is produced and stored in the α cells. The incretins only act on the release of insulin when the blood glucose level is high after eating. One advantage of this mode of action is that hypoglycemia (i.e. an excessive drop in blood sugar level with consequences up to cramps and unconsciousness) cannot occur when taking this active ingredient, which is possible with some other antidiabetic drugs . The inhibition of the release of glucagon also only takes place when the blood glucose level is increased.
Function of dipeptidyl peptidase-4
- see also main article: Dipeptidyl-peptidase-4
Dipeptidyl peptidase-4 ( DPP4 ) is an exopeptidase , it cleaves a dipeptide from proteins (at the N -terminal end) . The GLP-1 released from the intestine is inactivated within a few minutes and no longer contributes to lowering blood glucose levels.
Inhibitory effect of vildagliptin
Vildagliptin is a substrate of DPP4, unlike sitagliptin, which is a competitive inhibitor of DPP4. Vildagliptin slows down the breakdown of GLP-1 by inhibiting DPP4 and thereby creates a higher and longer-lasting GLP-1 concentration in the blood. The increased and prolonged presence of GLP-1 increases the body's own insulin production and release and slows down the release of glucagon. These effects lower the blood glucose level . As a DPP4 inhibitor, vildagliptin only works if GLP-1 is also formed at the same time and the blood sugar concentration is increased. This leads to a lower risk of hypoglycaemia compared to sulfonylureas or glinides . The lowering of the HbA1c value was detected during the intake of vildagliptin, which reflects the permanent lowering of the blood sugar level over the last 8 weeks before the HbA1c value measurement.
application areas
Vildagliptin is indicated for lowering blood sugar in diabetes mellitus when diet and exercise are inadequate and metformin is not suitable. Vildagliptin is used in a two- fold combination for the oral treatment of type 2 diabetes mellitus and is combined with either metformin , a sulfonylurea or a thiazolidinedione if the individual drug therapy is not sufficient to control the blood sugar adequately. The safety and effectiveness of vildagliptin in a triple combination, however, have not been proven. Therapy with vildagliptin also reduces the HbA1c value. The recommended daily dose for adults is either 50 mg or 50 mg twice a day, depending on the comedication (combination with sulphonylureas) or kidney function. Simultaneous food intake does not affect the effect.
Application restrictions
Vildagliptin must not be used (contraindications):
- in the presence of type 1 diabetes mellitus
- to treat ketoacidosis
- if you have severe liver problems, as it may increase transaminases (liver values)
- if you are pregnant
The use of vildagliptin is not recommended:
- in the presence of liver dysfunction
- in patients with moderate to severe renal impairment and in dialysis patients with end-stage renal disease due to limited experience
- in patients with NYHA grade III-IV heart failure due to lack of experience
- in patients under 18 years of age due to lack of data
Interactions
No interactions with other medicinal products were observed in the clinical studies. The likelihood of interactions is so low because vildagliptin is not metabolized via the cytochrome P450 superfamily and thus neither hampers the breakdown of cytochrome P450-metabolized active substances nor is their breakdown hindered and also does not induce a cytochrome P450 isoenzyme . Analogous to interactions with other antidiabetic drugs, the lowering of blood glucose levels may be impaired by thiazide diuretics , corticosteroids , thyroid drugs and sympathomimetics .
Side effects
During monotherapy with vildagliptin, hypoglycaemia and an increase in transaminases (liver enzymes) have occasionally occurred (at least in every thousandth test person and at most in every hundredth ). Such an increase in liver enzymes is an indication of possible liver damage. The liver values are to be checked during therapy. Due to possible liver damage, the drug must not be taken once a day as planned, but must be divided into two daily doses. Urinary tract infections, which in one study occurred almost three times more frequently than with placebo, are striking.
In combination with metformin, tremors , headaches , dizziness , hypoglycaemia (slightly more common than metformin + placebo), nausea and occasionally fatigue occurred frequently (at least in every hundredth test subject and at most in every tenth) .
In combination with a sulfonylurea, hypoglycaemia was common ( somewhat more frequently with vildagliptin and glimepiride than with placebo and glimepiride), tremor, headache, dizziness, asthenia and occasionally constipation . Nasopharyngitis (inflammation of the lining of the nose and throat ) has occurred very rarely (less than in every ten thousandth test person).
In combination with a thiazolidinedione, body weight gain and peripheral edema were commonly observed, occasionally headache and asthenia.
Benefit / risk assessment
Vildagliptin lowers HbA1c (a surrogate marker for blood sugar control) by 0.5% to 0.8% (50 mg) or 0.7% to 1.1% (100 mg) compared to placebo. This is slightly worse than other oral anti-diabetic drugs. Compared to rosiglitazone and metformin, non-inferiority could not be proven. No data are available on long-term safety or on the effect on late complications of diabetes mellitus.
Pharmacokinetics
Absorption
If the tablet with the active ingredient is taken on an empty stomach, the maximum plasma level is reached after 1.7 hours. If the tablet was taken after a meal, the then slightly lower maximum plasma level shifts to about 2.5 hours after intake. In both cases the bioavailability was 85%.
distribution
Vildagliptin has a plasma protein binding of 9.3%, which almost eliminates the risk of drug interactions due to plasma protein displacement. The volume of distribution at steady state after iv -Verabreichung is 71 liters, suggesting that vildagliptin is distributed not only in the blood circulation.
Metabolism
69% of the total dose of vildagliptin is metabolized. 57% of the total dose is hydrolyzed on the cyano group, with the inactive carboxylic acid metabolite being formed. 4% of the total dose is hydrolyzed at the amide bond. DPP4 also contributes in part to the hydrolysis of vildagliptin. Vildagliptin is not metabolised by isoenzymes of the cytochrome P450 superfamily (according to in vitro studies ).
elimination
About 85% of the total dose is excreted in the urine and 15% in the faeces . The elimination half-life is approximately 2 hours after intravenous administration and 3 hours after oral administration.
chemistry
The name of vildagliptin according to the IUPAC nomenclature is (2 S ) - {((3-Hydroxyadamantan-1-yl) amino) acetyl} pyrrolidine-2-carbonitrile; it is thus a derivative of adamantane . Vildagliptin is a white to slightly yellowish or slightly gray crystalline powder; polymorphic modifications are so far unknown. It is not hygroscopic and very soluble in water and organic solvents. Vildagliptin has one center of chirality and thus two enantiomers , of which only the ( S ) -enantiomer (the eutomer ) is used as a medicinal substance. The ( R ) -enantiomer is the biologically inactive distomer .
Trade names
Galvus (EU), Jalra (A), Xiliarx (A)
- with metformin : Eucreas (EU), Zomarist (A)
Web links
- Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Vildagliptin
Individual evidence
- ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1716.
- ↑ Novartis: GALVUMET (PDF; 183 kB).
- ↑ santa cruz biotechnology: vildagliptin
- ↑ There is not yet a harmonized classification for this substance . A labeling of (-) - (2S) -1 - [[(3-Hydroxytricyclo [3.3.1.1 [3,7]] dec-1-yl) amino] acetyl] pyrrolidine-2 is shown, which is derived from a self-classification by distributors -carbonitrile in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 12, 2020.
- ↑ EPAR ( memo of December 26, 2009 in the Internet Archive ) of the European Medicines Agency.
- ^ Resolution of the Federal Joint Committee on an amendment to the Drugs Directive ... of October 1, 2013. on: g-ba.de
- ^ Pharmaceutical newspaper Vildagliptin: Novartis takes preparations from the market. on: pharmische-zeitung.de , 26/2014.
- ↑ Novartis - Pharmaceuticals Division: Activity Report 2015 ( Memento of February 24, 2014 in the Internet Archive ), p. 8.
- ↑ Vildagliptin is back , apotheke adhoc, December 14, 2018.
- ^ Pharmaceutical newspaper . No. 44, 2007, p. 26 ff.
- ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 159 f.
- ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 160.
