Linagliptin

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Structural formula
Structure of linagliptin
General
Non-proprietary name Linagliptin
other names

8 - [(3 R ) -3-aminopiperidin-1-yl] -7- (but-2-yn-1-yl) -3-methyl-1 - [(4-methylquinazolin-2-yl) methyl] - 3,7-dihydro-1 H -purine-2,6-dione ( IUPAC )

Molecular formula C 25 H 26 N 8 O 2
External identifiers / databases
CAS number 668270-12-0
PubChem 10096344
ChemSpider 8271879
DrugBank DB08882
Wikidata Q909745
Drug information
ATC code

A10 BH05

Drug class

Antidiabetic drugs

Mechanism of action

DPP4 inhibitor

properties
Molar mass 472.54 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Linagliptin ( BI-1356 , brand name: Trajenta ® ) is a drug for the oral treatment of type 2 diabetes . In August 2011, the European Commission granted approval for the drug developed by the pharmaceutical company Boehringer Ingelheim . Linagliptin is an active ingredient from the group of dipeptidyl peptidase-4 inhibitors . These inhibit the enzyme dipeptidyl peptidase 4 (DPP-4).

pharmacology

Pharmacodynamics (mode of action)

Linagliptin is an inhibitor of the dipeptyl peptidase isoenzyme DPP-4, which it competitively and selectively inhibits against other isoenzymes such as the dipeptyl peptidases DPP-8 and DPP-9. As Dipeptylpeptidase-4 inhibitor to inhibit the degradation of the incretin - hormone glucagon-like peptide-1 (GLP-1). Compared to the gliptins sitagliptin , saxagliptin and vildagliptin , which were already commercially used in 2008 , linagliptin was characterized by a higher potency and a longer duration of action in cell cultures and in animal experiments on rats.

Pharmacokinetics

Many of the pharmacokinetic properties of linagliptin, such as clearance and volume of distribution , are non-linear and dose-dependent. The oral bioavailability of 10 mg linagliptin is 30%. In the organism, linagliptin is bound by its target protein, dipeptylpeptidase-4, and only a small percentage is metabolized. The elimination half-life is independent of the dose and is between 125 and 140 hours. Excretion occurs mainly via the gastrointestinal tract . About 5% of the oral dose is eliminated renally. This makes linagliptin the only one of the DPP4 inhibitors approved until 2011 that can be given independently of kidney function.

Admission / Health Policy

Linagliptin was approved by the European Commission in August 2011 . The 5 mg dose of the tablet is approved as monotherapy for type 2 diabetes mellitus, if metformin is intolerant or if metformin is contraindicated due to renal insufficiency . If required, the combination of linagliptin with metformin and the combination of linagliptin with metformin and sulfonylurea is also permitted.

In Germany, in connection with the early benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG), the drug has not yet been brought onto the market by the manufacturer Boehringer Ingelheim and its alliance partner Eli Lilly . For the early benefit assessment, the manufacturer did not submit the comparisons with the standard therapies with metformin and sulphonylureas in 2011, but instead compared linagliptin with other gliptins . The Institute for Quality and Efficiency in Health Care was therefore unable to certify any additional benefit for linagliptin compared to the standard therapies with metformin and sulfonylureas. The Federal Joint Committee gave the manufacturer the opportunity to initiate a new benefit assessment of the active ingredient at a later date on the basis of complete assessment documents. After a renewed benefit assessment in December 2012, the Institute for Quality and Efficiency in Health Care (IQWiG) came to the conclusion: “The assessment of the new dossier did not reveal any additional benefit of the active ingredient compared to the appropriate comparator therapy. Because the manufacturer has not submitted any relevant studies. ”Accordingly, the Federal Joint Committee decided in February 2013 for formal reasons that no additional benefit had been proven for linagliptin either in monotherapy or in dual combination therapy (linagliptin + metformin).

literature

Web links

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ↑ dpa: Boehringer booked another stage win. In: Handelsblatt. August 26, 2011.
  3. ↑ L. Thomas, M. Eckhardt, E. Langkopf, M. Tadayyon, F. Himmelsbach, M. Mark: (R) -8- (3-amino-piperidin-1-yl) -7-but-2-ynyl -3-methyl-1- (4-methyl-quinazolin-2-ylmethyl) -3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors . In: J. Pharmacol. Exp. Ther. tape 325 , no. 1 , April 2008, p. 175-182 , doi : 10.1124 / jpet.107.135723 , PMID 18223196 .
  4. ↑ a b S. Retlich, V. Duval, A. Ring et al .: Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg-10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects . In: Clin Pharmacokinet . tape 49 , no. December 12 , 2010, p. 829-840 , doi : 10.2165 / 11536620-000000000-00000 , PMID 21053992 .
  5. ^ S. Blech, E. Ludwig-Schwellinger, EU Gräfe-Mody, B. Withopf, K. Wagner: The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans . In: Drug Metab. Dispos. tape 38 , no. 4 , April 2010, p. 667-678 , doi : 10.1124 / dmd.109.031476 , PMID 20086031 .
  6. ↑ (EPAR summary for the public) (PDF; 120 kB) Approval notification Trajenta - Linagliptin, EMA, (more detailed information) accessed on July 29, 2012 (English).
  7. ↑ AMNOG slows down: no linagliptin in Germany , Pharmazeutische Zeitung online, September 5, 2011.
  8. ↑ Added benefit of linagliptin has not been proven (PDF; 24 kB), IQWiG press release of January 2, 2012.
  9. ↑ Early benefit assessment: G-BA makes six further decisions , G-BA press release of March 29, 2012.
  10. ↑ Linagliptin: Again, no evidence of added benefit , IQWiG press release of December 3, 2012.
  11. ^ Resolution of the Federal Joint Committee (PDF; 164 kB), G-BA resolution of February 21, 2013.
  12. ^ Lawsuit against benefit assessment: Pharmaceutical industry dismantles the cost damper for pills In: Der Spiegel Online, February 22, 2013.