Trovafloxacin

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Trovafloxacin
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa605016
Routes of
administration		Oral, intravenous
ATC code
Legal status
Legal status
  • Withdrawn from market
Identifiers
  • 7-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-[1,8] naphthyridine-3-carboxylic acid
JSmol)
  • O=C(O)C2=CN(c1nc(c(F)cc1C2=O)N3C[C@H]4[C@H](N)[C@H]4C3)c5ccc(F)cc5F
  • InChI=1S/C20H15F3N4O3/c21-8-1-2-15(13(22)3-8)27-7-12(20(29)30)17(28)9-4-14(23)19(25-18(9)27)26-5-10-11(6-26)16(10)24/h1-4,7,10-11,16H,5-6,24H2,(H,29,30)/t10-,11+,16+ checkY
  • Key:WVPSKSLAZQPAKQ-CDMJZVDBSA-N checkY
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Trovafloxacin (sold as Trovan by

fluoroquinolones
.

Adverse reactions

Trovafloxacin use is significantly restricted due to its high potential for inducing serious and sometimes fatal liver damage.[2] Currently, the drug is not approved for use in the U.S. or the European Union due to association with cases of acute liver failure and death.

Manufacturing

Trovafloxacin synthesis: K. E. Brighty, U.S. patent 5,164,402 (1992 to Pfizer).

The key reaction in building the ring consists of

Catalytic hydrogenation then removes the carbobenzyloxy protecting group to afford the secondary amine (8). In a standard quinoline reaction, this amine is then used to displace the more reactive fluorine at the 7-position in Ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (9).[3]

Society and culture

Legal status

The U.S. Food and Drug Administration approved trovafloxacin for therapeutic use in December 1997 for use in patients aged 18 years and older.[4] In June 1999, the agency advised doctors to limit the prescription of trovafloxacin due to adverse events associated with the drug (over 100 cases of acute liver injury reported to FDA). In May 2000, the FDA withdrew marketing authorisation for trovafloxacin.

Trovafloxacin received marketing authorisation in the European Union in October 1998.

Committee for Proprietary Medicinal Products recommended suspension of the marketing authorisation for a year.[6][7] The suspension took effect in August 1999 and was renewed in September 2000.[5] In October 2000, Pfizer notified the European Commission of its decision to voluntarily withdraw the marketing authorisation which was approved by EMA in March 2001.[5]

Economics

Trovan sales during its first full year on the market contributed US$160 million of Pfizer's total revenue of US$12.6 billion. Investors expected it to eventually bring in US$1 billion per year.[6]

Nigerian clinical trial controversy

Main article:
Kano Trovafloxacin trial litigation

In 1996, during a

Nigerian government or consent from the children's parents.[13] The case came to light in December 2000 as the result of an investigation by The Washington Post
, and sparked significant public outcry. The most serious error was the falsification and backdating of an ethics approval letter by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intramuscular ceftriaxone.

Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a

ruled that the Nigerian victims and their families were entitled to bring suit against Pfizer in the United States under the Alien Tort Statute. A US$75 million settlement with the State of Kano was reached on July 30, 2009.[14]
Additionally two lawsuits also remain pending in New York, United States.[14] According to Wikileaked US embassy cables, Pfizer's country manager admitted that "Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases."[15]

See also

References

  1. PMID 9124824
    .
  2. S2CID 43307678
    .
  3. ^ D. Lednicer, The organic chemistry of Drug Synthesis, Vol. 5, p 123 (1995).
  4. ^ "Trovafloxacin – Approval Letter & Printed Labelling" (PDF). Food and Drug Administration.
  5. ^ a b c "Public statement on Trovan / Trovan IV / Turvel / Turvel IV: Withdrawal of the marketing authorisations" (PDF). European Medicines Agency.
  6. ^ a b Petersen M (August 27, 2000). "Unforeseen Side Effects Ruined One Blockbuster". The New York Times. p. 3.11.
  7. ^ "Suspension of Trovan Drug in Europe Is Urged". The New York Times. June 12, 1999. p. C.3.
  8. ISBN 9781483350004
    . Retrieved 2019-01-21.
  9. ^ Report of the Investigation Committee on the Clinical Trial of Trovafloxacin (Trovan) by Pfizer, Kano, 1996. (PDF), Federal Ministry of Health, Nigeria
  10. S2CID 1325773
    .
  11. PMID 10064255
    .
  12. PMID 23240173
    .
  13. ^ Stephens J (May 7, 2006). "Panel Faults Pfizer in '96 Clinical Trial In Nigeria". The Washington Post. p. A01. Retrieved 2006-08-28.
  14. ^ a b Stephens J (July 31, 2009). "Pfizer to Pay $75 Million to Settle Nigerian Trovan Drug-Testing Suit". The Washington Post. Retrieved May 26, 2010.
  15. ^ Boseley S (9 December 2010). "WikiLeaks cables: Pfizer 'used dirty tricks to avoid clinical trial payout'". The Guardian.

External links

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