Posaconazole

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Posaconazole
Posaconazole.svg
Posaconazole3d.png
Systematic (IUPAC) name
4-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-1,2,4-triazol-3-one
Clinical data
Trade names Noxafil, Posanol
AHFS/Drugs.com monograph
MedlinePlus a607036
Licence data EMA:Link, US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability High
Protein binding 98 to 99%
Metabolism Hepatic glucuronidation
Half-life 16 to 31 hours
Excretion Fecal (77%) and renal (14%)
Identifiers
CAS number 171228-49-2 YesY
ATC code J02AC04
PubChem CID 147912
DrugBank DB01263
ChemSpider 130409 YesY
UNII 6TK1G07BHZ YesY
KEGG D02555 YesY
ChEBI CHEBI:64355 N
ChEMBL CHEMBL1397 N
Synonyms 4-{4-[4-(4-{[(5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one
Chemical data
Formula C37H42F2N8O4 
Mol. mass 700.778 g/mol
 N (what is this?)  (verify)

Posaconazole is a triazole antifungal drug[1][2] marketed in the United States, the European Union, and in other countries by Schering-Plough under the trade name Noxafil. In Canada, posaconazole is marketed by Schering-Plough under the trade name Posanol.

Pharmacology[edit]

Mode of action[edit]

Posaconazole works by disrupting the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems such as ATPase and enzymes of the electron transport system, thus inhibiting growth of the fungi. It does this by blocking the synthesis of ergosterol by inhibiting of the enzyme lanosterol 14α-demethylase and accumulation of methylated sterol precursors. Posaconazole is significantly more potent at inhibiting 14-alpha demethylase than itraconazole.[3][4][5]

Microbiology[edit]

Posaconazole is active against the following microorganisms:[3][6]

Pharmacokinetics[edit]

Posaconazole is absorbed within three to five hours. It is predominately eliminated through the liver, and has a half life of about 35 hours. Oral administration of posaconazole taken with a high-fat meal exceeds 90% bioavailability and increases the concentration by four times compared to fasting state.[6][7]

Clinical use[edit]

It is used to treat invasive infections by Candida species,[8] Mucor, and Aspergillus species[9] in severely immunocompromised patients.

Clinical evidence for its utility in treatment of invasive disease caused by Fusarium species (fusariosis) is limited.[10]

Two studies suggest posaconazole may be superior to other triazoles, such as fluconazole or itraconazole, in the prevention of invasive fungal infections, although it may cause more serious side effects.[11][12]

There is also some indication that posaconazole may be the most effective treatment for both chronic and acute Chagas disease, showing much better efficacy than benznidazole.[13] Schering-Plough is currently recruiting participants for a phase 2 clinical trial in Argentina to test its efficacy against asymptomatic, chronic Chagas.[14]

References[edit]

  1. ^ Schiller DS, Fung HB (September 2007). "Posaconazole: an extended-spectrum triazole antifungal agent". Clin Ther 29 (9): 1862–86. doi:10.1016/j.clinthera.2007.09.015. PMID 18035188. 
  2. ^ Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH (October 2008). "Posaconazole: an oral triazole with an extended spectrum of activity". Ann Pharmacother 42 (10): 1429–38. doi:10.1345/aph.1L005. PMID 18713852. 
  3. ^ a b Brunton L, Lazo J, Parker K. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. San Francisco: McGraw-Hill; 2006. ISBN 978-0-07-142280-2
  4. ^ "Clinical Pharmacology Pasoconazole". Retrieved 18 February 2010. 
  5. ^ "Daily Med, Product Information Noxafil". Retrieved 18 February 2010. 
  6. ^ a b Dodds Ashley, Elizabeth; Perfect, John (October 13, 2009). "Pharmacology of azoles". Retrieved 18 February 2010. 
  7. ^ "Drugs at FDA: Noxafil". Retrieved 18 February 2010. 
  8. ^ Li X, Brown N, Chau AS, et al. (January 2004). "Changes in susceptibility to posaconazole in clinical isolates of Candida albicans". J. Antimicrob. Chemother. 53 (1): 74–80. doi:10.1093/jac/dkh027. PMID 14657086. 
  9. ^ Walsh TJ, Raad I, Patterson TF, et al. (January 2007). "Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial". Clin. Infect. Dis. 44 (1): 2–12. doi:10.1086/508774. PMID 17143808. 
  10. ^ Raad I, Hachem R, Herbrecht R, et al. (2006). "Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions". Clin Infect Dis 42 (10): 1398–1403. 
  11. ^ Cornely O, Maertens J, Winston D, Perfect J, Ullmann A, Walsh T, Helfgott D, Holowiecki J, Stockelberg D, Goh Y, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D (2007). "Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia". N Engl J Med 356 (4): 348–59. doi:10.1056/NEJMoa061094. PMID 17251531. 
  12. ^ Ullmann A, Lipton J, Vesole D, Chandrasekar P, Langston A, Tarantolo S, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S (2007). "Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease". N Engl J Med 356 (4): 335–47. doi:10.1056/NEJMoa061098. PMID 17251530. 
  13. ^ "Am J Trop Med Hyg April 2010 vol. 82 no. 4"
  14. ^ "A Study of the Use of Oral Posaconazole (POS) in the Treatment of Asymptomatic Chronic Chagas Disease (P05267 AM1) (STOP CHAGAS)"