Article: Telithromycin

Telithromycin
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
Identifiers
CAS number	191114-48-4
ATC code	J01FA15
PubChem	5462516
DrugBank	APRD00483
Chemical data
Formula	C43H65N5O10
Mol. weight	812.004 g/mol
Pharmacokinetic data
Bioavailability	57%
Protein binding	60% to 70%
Metabolism	Hepatic (50% CYP3A4-mediated)
Half life	10 hours
Excretion	Biliary and renal
Therapeutic considerations
Pregnancy cat.	C (U.S.)
Legal status	POM (UK), ℞-only (U.S.)
Routes	Oral

Telithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek®.

Telithromycin is a semi-synthetic erythromycin derivative. It is created by substituting the cladinose sugar with a ketogroup 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, like in clarithromycin, to achieve better acid-stability.

Questions of Telithromycin Safety Under Public and Congressional Scrutiny

In the first half of July, controversy of telithromycin was sparked when the New York Times reported that David Graham, one of many FDA safety officials concerned about safety of the antibiotic in both adults and children, wrote in an E-mail message to another agency official that the drug's approval was in error. Concern focuses on the drug's liver toxicity, but also extends to vision problems and other neurogenic effects (reported blackouts/syncopal episodes), including potentially mortal consequences of myasthenia gravis. Liver failure has been reported in fourteen adult patients, four of which died, and another twenty-three sustaining "serious liver injury," according to The Times July 18 article "Approval of Antibiotic Worried Safety Officials". The Times also published excerpts of Dr. Graham's internal memorandum, including this quote: “It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned,” Dr. Graham wrote. In the memo, he subsequently advised "immediate withdrawal."http://www.nytimes.com/2006/07/19/health/19fda.html The Times characterized the internal FDA climate as a "fierce battle," a climate which is most likely fueled by the increased press attention in recent months (F.D.A. Warns of Liver Failure After Antibiotic (June 30, 2006), and Halt Is Urged for Trials of Antibiotic in Children (June 8, 2006). Including Dr. Graham, three other FDA officials have been named as critics of the drug: Dr. Charles Cooper, Dr. David Ross and Dr. Rosemary Johann-Liang. Bipartisan congressional interest has also been triggered. The Times reports that Senator Charles E. Grassley (R-Iowa, chairman, Senate Finance Committee) is "investigating" the issue with Representatives Edward J. Markey (D-Mass) and Henry A. Waxman (D-Calif). Although claiming to receive more than "dozens" of messages (presumably e-mails), The Times did not disclose the source.

History

French pharmaceutical company Hoechst Marion Roussel (later Aventis) started phase II/III trials of telithromycin (HMR-3647) in 1998. Telithromycin was approved by the European Commission in July 2001 and subsequently came on sale in October 2001. In USA, telithromycin gained FDA approval April 1, 2004 .

Available forms

Telithromycin is administered as tablets. Two 400mg tablets to be taken together, daily, with 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 thus inhibits the translocation of peptides. Telithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, telithromycin binds simultaneously in to two domains of 23S RNA of the ribosomal subunit 50S, where older macrolides bind only in one. 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 without 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 much higher than in plasma.

Metabolism

It 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 into the bile and urine, the biliary route being favoured. Telithromycin's half-life is approximately 10 hours.

Side effects

Most common side-effects are gastrointestinal; diarrhoea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision and rashes.

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.

There have been 4 reported cases of fatal liver failure linked to telithromycin, and 23 reported cases of liver-related injury caused by the Drug.

Telithromycin has been known to cause false positive readings in drug screenings for cocaine and amphetamines.