Telithromycin
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| Systematic (IUPAC) name |
(1S,2R,5R,7R,8R,9S,11R,13R,14R)-8-[(2S,3R,4S,6R)-
4-dimethylamino-3-hydroxy-6-methyl-oxan-2-yl]oxy-
2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-15-
[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-3,17-dioxa-15-
azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone |
| Clinical data |
| Trade names |
Ketek |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a604026 |
| Pregnancy cat. |
C (U.S.) |
| Legal status |
POM (UK), ℞-only (U.S.) |
| Routes |
Oral |
| Pharmacokinetic data |
| Bioavailability |
57% |
| Protein binding |
60% to 70% |
| Metabolism |
Hepatic (50% CYP3A4-mediated) |
| Half-life |
10 hours |
| Excretion |
Biliary and renal |
| Identifiers |
| CAS number |
191114-48-4 Y |
| ATC code |
J01FA15 |
| PubChem |
CID 5462516 |
| DrugBank |
DB00976 |
| ChemSpider |
2273373 Y |
| UNII |
KI8H7H19WL Y |
| KEGG |
D01078 N |
| ChEMBL |
CHEMBL1136 Y |
| Chemical data |
| Formula |
C43H65N5O10 |
| Mol. mass |
812.004 g/mol |
SMILES
- O=C2[C@@H]([C@@H](O[C@@H]1O[C@@H](C[C@H](N(C)C)[C@H]1O)C)[C@@](OC)(C)C[C@H](C(=O)[C@H](C)[C@H]3N(C(=O)O[C@]3(C)[C@H](OC(=O)[C@@H]2C)CC)CCCCn4cc(nc4)c5cccnc5)C)C
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InChI
-
InChI=1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33-,36-,37-,38-,40+,42-,43-/m1/s1 Y
Key:LJVAJPDWBABPEJ-PNUFFHFMSA-N Y
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N (what is this?) (verify)
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Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant controversy regarding safety and research fraud, the US Food and Drug Administration sharply curtailed the approved uses of the drug in 2007.
Telithromycin is a semi-synthetic erythromycin derivative. It is created by substituting a ketogroup for the cladinose sugar and adding a carbamate ring in the lactone ring. An alkyl-aryl moiety is attached to this carbamate ring. Furthermore, the carbon at position 6 has been methylated, as is the case in clarithromycin, to achieve better acid-stability.
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Contents
- 1 History
- 1.1 Development and approval
- 1.2 Safety controversies and fraud
- 1.3 FDA Warning
- 2 Available forms
- 3 Mechanism of action
- 4 Pharmacokinetics
- 5 Metabolism
- 6 Adverse effects
- 7 References
- 8 External links
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History
Development and approval
French pharmaceutical company Hoechst Marion Roussel (later Sanofi-Aventis) began phase II/III clinical trials of telithromycin (HMR-3647) in 1998. Telithromycin was approved by the European Commission in July 2001 and subsequently went on sale in October 2001. In the US, telithromycin received U.S. Food and Drug Administration (FDA) approval on April 1, 2004 .
Safety controversies and fraud
FDA staffers publicly complained that safety problems and data integrity issues were ignored prior to approval, and the House Committee on Energy and Commerce held hearings to examine these complaints. One doctor went to prison because she falsified data in her portion of the clinical trials because Ketek seemed to cause liver problems, including liver failure, to a greater extent than would be expected of a common-use antibiotic.[1] The House Committee on Energy and Commerce held hearings.[2]
Study 3014 was a key clinical trial of more than 24,000 patients which Sanofi-Aventis submitted to the FDA seeking approval for Ketek. The doctor who treated the most patients in Study 3014, Maria "Anne" Kirkman Campbell, is currently serving a 57-month sentence in federal prison after pleading guilty to defrauding Aventis and others. The indictment states that Campbell fabricated data she sent to the company.[3] Documents including internal Sanofi-Aventis emails show that Aventis was worried about Campbell early in study 3014 but didn't tell the FDA until the agency's own inspectors discovered the problem independently.[4]
In July 2006, the New York Times[5] quoted e-mails from FDA safety official David Graham, arguing that telithromycin had not been proven safe, that safer drugs were available for the same indications, and that the approval was a mistake and should be immediately withdrawn. There were 14 cases of liver failure, including at least four deaths,[6] vision problems, blackouts, syncope, and potentially fatal cases of myasthenia gravis. Graham wrote, “It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned.” [5] The Times said that the FDA was embroiled in a "fierce battle" over the approval, fueled by exposure in the press. Two other FDA officials also criticized the approval: David Ross and Rosemary Johann-Liang, who wrote, "How does one justify balancing the risk of fatal liver failure against one day less of ear pain?".[5] Senator Charles E. Grassley (R-Iowa, chairman, Senate Finance Committee), Representatives Edward J. Markey (D-Mass) and Henry A. Waxman (D-Calif) held hearings.
FDA Warning
On February 12, 2007, the FDA announced a revision to the labeling of Ketek to improve patient safety. The changes included the removal of two of the three previously approved indications: acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. The agency determined that the balance of benefits and risks no longer supported approval of the drug for these indications. Ketek will remain on the market for the treatment of community acquired pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities). In addition, the FDA worked with the manufacturer to update the product labeling with a "black box warning," their strongest form of warning. Ketek's warning states that it should not be used in patients with myasthenia gravis, a disease that causes muscle weakness.[7]
Available forms
Telithromycin is administered as tablets. The standard dosing is two 400 mg tablets to be taken together daily, with or without food.
Mechanism of action
Telithromycin prevents bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to the subunit 50S of the bacterial ribosome, and blocks the progression of the growing polypeptide chain. Telithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, telithromycin strongly bind simultaneously to two domains of 23S RNA of the 50 S ribosomal subunit, where older macrolides bind strongly only to one domain and weakly to the second domain. Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S.
Pharmacokinetics
Unlike erythromycin, telithromycin is acid-stable and can therefore be taken orally while being protected from gastric acids. It is fairly rapidly absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, telithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of telithromycin is released. The concentration of telithromycin in the tissues is much higher than in plasma.Telithromycin fulfills a role that has arisen due to the rise of microbial resistance to existing macrolides and appears to be effective against macrolide-resistant Streptococcus pneumoniae. The defining differentiating characteristic of the ketolides as opposed to other macrolides is the removal of the neutral sugar, L-cladinose from the 3 position of the macrolide ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group.[8]
Metabolism
Telithromycin is metabolized mainly in the liver, the main elimination route being the bile, a small portion is also excreted into the urine. About one third is excreted unchanged in bile and urine, the biliary route being favoured. Telithromycin's half-life is approximately ten hours.
Adverse effects
Most common side-effects are gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision, and rashes. Prolonged QTc intervals may also be caused by telithromycin.[9]
Rare but severe side effects reported in January 2006 involve damage to the liver. Three different incidents have been reported: one ending in death, one in a liver transplant and one case of drug-induced hepatitis.[6]
In the United States the FDA's Office of Epidemiology and Surveillance identified 12 cases of acute liver failure, resulting in four deaths, and an additional 23 cases of acute, serious liver injury in patients taking telithromycin up to April 2006.[10]
Telithromycin has been known to cause false positive readings in drug screenings for cocaine and amphetamines.[citation needed]
By April 2008, independent analysis using FDA data has linked Ketek (Telithromycin) to 18 deaths and at least 134 cases of liver damage. Some researchers say the total may be far greater.[11]
In 2010, a published report described the likely mechanism of action underlying not only the cases of liver failure but also cases of visual disturbances and exacerbations of myasthenia gravis. The study showed that a pyridine moiety that is part of the telithromycin molecule acts as an antagonist on cholinergic receptors located in the neuromuscular junction, the ciliary ganglion of the eye and the vagus nerve innervating the liver. Other macrolides, such as azithromycin and clarithromycin and the fluoroketolide, solithromycin, do not contain the pyridine moiety and do not antagonize these cholinergic receptors significantly.[12]
References
- ^ Splete, Heidi; Kerri Wachter (March 2006). "Liver toxicity reported with Ketek". Internal Medicine News.
- ^ [1] House of Representatives, The House Committee on Energy and Commerce, Honorable John D. Dingell, Chairman, Subcommittee on Oversight and Investigations, "The Adequacy of FDA Efforts to Assure the Safety of the Drug Supply", February 13, 2007.
- ^ [2] Food and Drug Administration, NOTICE OF INITIATION OF DISQUALIFICATION PROCEEDINGS AND OPPORTUNITY TO EXPLAIN (NIDPOE), Leslie Ball, 5/18/2006
- ^ [3] Infected Data: Fraud, Errors Taint Key Study Of Widely Used Sanofi Drug Despite Some Faked Results, FDA Approves Antibiotic; One Doctor's Cocaine Use; Company Defends Safety, By ANNA WILDE MATHEWS, Wall Street Journal, May 1, 2006
- ^ a b c Harris, G . (2006-07-19). "Approval of Antibiotic Worried Safety Officials". The New York Times 19 July 2006. http://www.nytimes.com/2006/07/19/health/19fda.html. Retrieved 2010-05-25.
- ^ a b Clay KD et al. (2006). "Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review". Annals of Internal Medicine 144 (6): 415–420. PMID 16481451.
- ^ http://www.fda.gov/bbs/topics/NEWS/2007/NEW01561.html
- ^ Scheinfeld N. Telithromycin: A brief review of a new ketolide antibiotic. J Drug Dermat 2004;3:409-13. PMID 15303785
- ^ Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e McGraw-Hill 2009 via "accessmedicine.com"
- ^ http://www.fda.gov/ohrms/dockets/AC/06/slides/2006-4266s1-01-07-FDA-Brinker.ppt
- ^ http://www.rd.com/national-interest/consumer-safety/fda-approves-harmful-antibiotic/article.html
- ^ D Bertrand, S Bertrand, E Neveu, and P Fernandes (2010). Molecular Characterization of Off-Target Activities of Telithromycin: a Potential Role for Nicotinic Acetylcholine Receptors. Antimicrobial Agents and Chemotherapy. 54: 5399-5402
External links
- FDA Public Health Advisory for Telithromycin (marketed as Ketek)
- Article in Annals of Internal Medicine regarding cases of hepatotoxicity induced by telithromycin
- New York Times article. Login is required
- FDA officials question safety of antibiotic 'Ketek'
- Drugs and Treatments - KETEK Oral - Patient Handout from WebMD
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Antibacterials: protein synthesis inhibitors (J01A, J01B, J01F, J01G, QJ01XQ)
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|
| 30S |
Aminoglycosides
(initiation inhibitors) |
| -mycin (Streptomyces) |
- Streptomycin#
- Dihydrostreptomycin
- Neomycin#
- Framycetin
- Paromomycin
- Ribostamycin
- Kanamycin#
- Amikacin
- Arbekacin
- Bekanamycin
- Dibekacin
- Tobramycin
- Spectinomycin#
- Hygromycin B
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|
| -micin (Micromonospora) |
- Gentamicin#
- Netilmicin
- Sisomicin
- Isepamicin
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Tetracycline antibiotics
(tRNA binding) |
| Tetracyclines |
- Doxycycline#
- Chlortetracycline
- Clomocycline
- Demeclocycline
- Lymecycline
- Meclocycline
- Metacycline
- Minocycline
- Oxytetracycline
- Penimepicycline
- Rolitetracycline
- Tetracycline
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| Glycylcyclines |
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| 50S |
Oxazolidinone
(initiation inhibitors) |
- Linezolid
- Torezolid
- Eperezolid
- Posizolid
- Radezolid
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| Peptidyl transferase |
| Amphenicols |
- Chloramphenicol#
- Azidamfenicol
- Thiamphenicol
- Florfenicol
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| Pleuromutilins |
- Retapamulin
- Tiamulin
- Valnemulin
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| MLS (transpeptidation/translocation) |
| Macrolides |
- Azithromycin#
- Clarithromycin
- Dirithromycin
- Erythromycin#
- Flurithromycin
- Josamycin
- Midecamycin
- Miocamycin
- Oleandomycin
- Rokitamycin
- Roxithromycin
- Spiramycin
- Troleandomycin
- Tylosin
- Ketolides
- Telithromycin
- Cethromycin
- Solithromycin
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| Lincosamides |
- Clindamycin#
- Lincomycin
- Pirlimycin
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| Streptogramins |
- Pristinamycin
- Quinupristin/dalfopristin
- Virginiamycin
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| EF-G |
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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gr+f/gr+a(t)/gr-p(c)/gr-o
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