Dapagliflozin

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Dapagliflozin
Dapagliflozin skeletal.svg
Haworth projection of dapagliflozin.svg
Haworth projection (bottom)
Clinical data
Pronunciation /ˌdæpəɡlˈflzɪn/ DAP-ə-glif-LOH-zin
Trade names Forxiga, Farxiga
AHFS/Drugs.com UK Drug Information
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 78% (after 10 mg dose)
Protein binding ~91%
Metabolism UGT1A9 (major), CYP (minor)
Metabolites Dapagliflozin 3-O-glucuronide (inactive)
Biological half-life ~12.9 hours
Excretion Urine (75%), feces (21%)[1]:5
Identifiers
Synonyms BMS-512148; (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.167.331
Chemical and physical data
Formula C21H25ClO6
Molar mass 408.873 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Dapagliflozin (INN,[2] USAN,[3] trade name Farxiga /fɑːrˈsɡə/ far-SEE-gə in the U.S. and Forxiga in the EU and Russia) is a drug of the gliflozin class, used to treat type 2 diabetes. It was developed by Bristol-Myers Squibb in partnership with AstraZeneca.

Medical uses[edit]

In July 2011 a U.S. Food and Drug Administration (FDA) endocrinologic and metabolic drugs advisory committee recommended against approval until more data were available.[4]

The FDA approved dapagliflozin on January 8, 2014 for glycemic control, along with diet and exercise, in adults with type 2 diabetes.[5]

In 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion on the drug.[6] It is now marketed in a number of European countries.[7]

The FDA approved the combination product dapagliflozin and metformin hydrochloride extended-release, called Xigduo XR, in October 2014.[8]

In Feb 2017 the FDA approved a once-daily combination of dapagliflozin 10 mg and saxagliptin 5 mg, as Qtern.[9]

Side effects[edit]

Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day) it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes) which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Dapagliflozin is also associated with hypotensive reactions. There are concerns it may increase the risk of diabetic ketoacidosis.[10]

Mechanism of action[edit]

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[11] In clinical trials, dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to metformin.[12]

Selectivity[edit]

The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.[13]

Research[edit]

Clinical trials to assess effectiveness for patients with type 1 diabetes are underway.[14][15]

References[edit]

  1. ^ "Farxiga (dapagliflozin) Tablets, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca Pharmaceuticals. Retrieved 15 November 2016. 
  2. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 59" (PDF). World Health Organization. 2008. p. 50. Retrieved 15 November 2016. 
  3. ^ "Statement on a Nonproprietary Name Adopted by the USAN Council" (PDF). American Medical Association. Archived from the original (PDF) on 7 February 2012. Retrieved 15 November 2016. 
  4. ^ "FDA Panel Advises Against Approval of Dapagliflozin". Healio. 19 July 2011. 
  5. ^ "FDA Approves Farxiga to Treat Type 2 Diabetes". Food and Drug Administration. 8 January 2014. Retrieved 15 November 2016. 
  6. ^ "Forxiga EPAR summary for the public" (PDF). European Medicines Agency. 12 November 2012. 
  7. ^ Drugs.com: International Drug Names for Forxiga.
  8. ^ "US FDA Approves Once-Daily Xigduo™ XR Tablets for Adults with Type 2 Diabetes". www.astrazeneca.com. AstraZeneca. 30 October 2014. 
  9. ^ [1]
  10. ^ "Safety Alerts for Human Medical Products — SGLT2 inhibitors: Drug Safety Communication — FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood". Food and Drug Administration. 15 May 2015. Retrieved 15 November 2016. 
  11. ^ Prous Science: Molecule of the Month November 2007
  12. ^ UEndocrine: Internet Endocrinology Community
  13. ^ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
  14. ^ Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin, ClinicalTrials.gov, April 2009
  15. ^ Trial Details for Trial MB102-020, Bristol-Myers Squibb, May 2009

External links[edit]