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Identification
Name Posaconazole
Accession Number DB01263
Type small molecule
Groups approved
Description

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • posaconazole
Brand names
  • Noxafil
Brand name mixtures Not Available
Categories
  • Trypanocidal Agents
  • Antibiotics, Antifungal
CAS number 171228-49-2
Weight Average: 700.7774
Monoisotopic: 700.329708282
Chemical Formula C37H42F2N8O4
InChI Key InChIKey=RAGOYPUPXAKGKH-AGDNISCASA-N
InChI
InChI=1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1
Plain Text
IUPAC Name
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
SMILES
CC[C@@H]([C@H](C)O)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OCC2CO[C@](CN3C=NC=N3)(C2)C2=C(F)C=C(F)C=C2)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzyl Alcohols and Derivatives
  • Phenols and Derivatives
  • Ethers
  • Phenethylamines
  • Anisoles
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Triazoles
  • Phenols and Derivatives
  • Aliphatic and Aryl Amines
  • Piperazines
  • Ethers
  • Benzene and Derivatives
  • Halobenzenes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Furans
  • Cyanamides
  • Alcohols and Polyols
  • Aryl Halides
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals.
Pharmacodynamics Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action.
Mechanism of action As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death.
Absorption Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
Volume of distribution
  • 1774 L
Protein binding Posaconazole is highly protein bound (>98%), predominantly to albumin.
Metabolism

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Route of elimination The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Half life Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).
Clearance
  • 32 L/hr
  • 51 L/hr [Single-Dose Suspension Administration of 200 mg, fasted]
  • 21 L/hr [Single-Dose Suspension Administration of 200 mg, nonfat meal]
  • 14 L/hr [Single-Dose Suspension Administration of 200 mg, high fat meal]
  • 91 L/hr [Single-Dose Suspension Administration of 400 mg, fasted]
  • 43 L/hr [Single-Dose Suspension Administration of 400 mg with liquid nutritional supplement (14 g fat)]
Toxicity During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.
Affected organisms
  • Aspergillis, Candida and other fungi
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Schering corp
Packagers
Dosage forms
Form Route Strength
Suspension Oral
Prices
Unit description Cost Unit
Noxafil 40 mg/ml suspension 7.08 USD ml
Patents
Country Patent Number Approved Expires
United States 5661151 1999-07-19 2019-07-19
United States 5703079 1994-08-26 2014-08-26
Canada 2305803 2009-12-22 2018-10-05
Canada 2179396 2001-04-17 2014-12-20
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Insoluble PhysProp
logP 5.5 PhysProp
Predicted Properties
Property Value Source
water solubility 1.20e-02 g/l ALOGPS
logP 4.71 ALOGPS
logP 5.41 ChemAxon Molconvert
logS -4.77 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 9 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 111.79 ChemAxon Molconvert
rotatable bond count 12 ChemAxon Molconvert
refractivity 200.71 ChemAxon Molconvert
polarizability 74.25 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007 Jan 25;356(4):348-59. Pubmed
  2. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007 Jan 25;356(4):335-47. Pubmed
  3. Bhattacharya M, Rajeshwari K, Dhingra B: Posaconazole. J Postgrad Med. 2010 Apr-Jun;56(2):163-7. Pubmed
  4. Frampton JE, Scott LJ: Posaconazole : a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68(7):993-1016. Pubmed
  5. Schiller DS, Fung HB: Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007 Sep;29(9):1862-86. Pubmed
  6. Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78. Pubmed
  7. Groll AH, Walsh TJ: Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005 Aug;3(4):467-87. Pubmed
  8. Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH: Posaconazole: an oral triazole with an extended spectrum of activity. Ann Pharmacother. 2008 Oct;42(10):1429-38. Epub 2008 Aug 19. Pubmed
  9. Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H: Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010 Jun;49(6):379-96. doi: 10.2165/11319340-000000000-00000. Pubmed
External Links
Resource Link
KEGG Drug D02555 Link_out
PubChem Compound 147912 Link_out
PubChem Substance 46508639 Link_out
ChemSpider 130409 Link_out
Therapeutic Targets Database DAP001101 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic/noxafil.htm Link_out
Drugs.com http://www.drugs.com/cdi/posaconazole-suspension.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Posaconazole Link_out
ATC Codes
  • J02AC04
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (182.9 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Cytochrome P450 51

Pharmacological action: yes
Actions: antagonist

Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol

Organism class: fungal
UniProt ID: P10613 Link_out
Gene: ERG11
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Chau AS, Mendrick CA, Sabatelli FJ, Loebenberg D, McNicholas PM: Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31. Pubmed
  4. Li X, Brown N, Chau AS, Lopez-Ribot JL, Ruesga MT, Quindos G, Mendrick CA, Hare RS, Loebenberg D, DiDomenico B, McNicholas PM: Changes in susceptibility to posaconazole in clinical isolates of Candida albicans. J Antimicrob Chemother. 2004 Jan;53(1):74-80. Epub 2003 Dec 4. Pubmed
  5. Bhattacharya M, Rajeshwari K, Dhingra B: Posaconazole. J Postgrad Med. 2010 Apr-Jun;56(2):163-7. Pubmed
  6. Schiller DS, Fung HB: Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007 Sep;29(9):1862-86. Pubmed
  7. Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78. Pubmed
  8. Groll AH, Walsh TJ: Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005 Aug;3(4):467-87. Pubmed
  9. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
  10. Warrilow AG, Melo N, Martel CM, Parker JE, Nes WD, Kelly SL, Kelly DE: Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B. Antimicrob Agents Chemother. 2010 Oct;54(10):4225-34. Epub 2010 Jul 26. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nagappan V, Deresinski S: Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007 Dec 15;45(12):1610-7. Pubmed
  2. Kharuzhyk SA, Matskevich SA, Filjustin AE, Bogushevich EV, Ugolkova SA: Survey of computed tomography doses and establishment of national diagnostic reference levels in the Republic of Belarus. Radiat Prot Dosimetry. 2010 Apr-May;139(1-3):367-70. Epub 2010 Feb 24. Pubmed
  3. Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nagappan V, Deresinski S: Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. Clin Infect Dis. 2007 Dec 15;45(12):1610-7. Pubmed
Comments
Drug created on May 16, 2007 11:41 / Updated on August 07, 2011 09:01

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.