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Posaconazole

PubChem CID
468595
Structure
Posaconazole_small.png
Molecular Formula
Synonyms
  • Posaconazole
  • 171228-49-2
  • Noxafil
  • Sch 56592
  • SCH-56592
Molecular Weight
700.8 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-08-01
  • Modify:
    2025-01-18
Description
Posaconazole is an N-arylpiperazine that consists of piperazine carrying two 4-substituted phenyl groups at positions 1 and 4. A triazole antifungal drug. It has a role as a trypanocidal drug. It is a member of triazoles, a N-arylpiperazine, an organofluorine compound, a member of oxolanes, an aromatic ether, a conazole antifungal drug and a triazole antifungal drug.
Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.
Posaconazole is an Azole Antifungal.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Posaconazole.png

1.2 3D Status

Conformer generation is disallowed since too many atoms

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 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
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RAGOYPUPXAKGKH-XAKZXMRKSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC[C@@H]([C@H](C)O)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5C[C@](OC5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C37H42F2N8O4
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 Deprecated CAS

177571-33-4

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 Pharos Ligand ID

2.3.14 RXCUI

2.3.15 Wikidata

2.3.16 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 4-(p-(4-(p-(((3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl)methoxy)phenyl)-1-piperazinyl)phenyl)-1-((1S,2S)-1-ethyl-2-hydroxypropyl)-delta(sup 2)-1,2,4-triazolin-5-one
  • Noxafil
  • posaconazole
  • posaconazole hydrate
  • SCH 56592
  • SCH-56592

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
700.8 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
4.6
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
11
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
12
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
700.32970817 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
700.32970817 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
112 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
51
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1170
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
4
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Color / Form

White solid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365

3.2.2 Melting Point

170-172 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365

3.2.3 Solubility

Insoluble

3.2.4 LogP

5.5

3.2.5 Dissociation Constants

pKa = 2.27 (1,2,4-triazole amine)
Physicians Desk Reference. 59th ed. Thomson PDR. Montvale, NJ 2005., p. 8-42

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antifungal Agents; Trypanocidal Agents; 14-alpha Demethylase Inhibitors
Human drug -> Prescription; Discontinued
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (POSACONAZOLE)
Human drugs -> Antimycotics for systemic use -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug
3.3.1.2 Animal Drugs
Active Ingredients (posaconazole) -> FDA Greenbook
Pharmaceuticals -> UK Veterinary Medicines Directorate List
S104 | UKVETMED | UK Veterinary Medicines Directorate's List | DOI:10.5281/zenodo.7802119

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

1 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+2H]+
Precursor m/z
351.173
Instrument
qTof
Ionization Mode
positive
Top 5 Peaks

342.168579 100

351.173737 92.35

342.669495 79.21

351.674377 64.60

308.136566 64.37

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Thumbnail
2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
701.337
Instrument
qTof
Ionization Mode
positive
Top 5 Peaks

701.336670 100

702.337830 39.63

683.323547 14.65

614.291321 11.19

546.229126 7.14

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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug 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.
Posaconazole AHCL oral suspension is indicated for use in the treatment of the following fungal infections in adults: Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products; Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products. Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Posaconazole AHCL oral suspension is also indicated for prophylaxis of invasive fungal infections in the following patients: Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections; Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.

7.2 LiverTox Summary

Posaconazole is a potent triazole antifungal agent used in the prevention of invasive fungal infections due to aspergillosis and candida in high risk patients. Posaconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a suspected but rare cause of clinically apparent acute drug induced liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antifungal Agents; Trypanocidal Agents; 14-alpha Demethylase Inhibitors
Antifungal Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 FDA Green Book

7.8 Drug Labels

Drug and label
Active ingredient and drug

7.9 Clinical Trials

7.9.1 ClinicalTrials.gov

7.9.2 EU Clinical Trials Register

7.10 EMA Drug Information

1 of 5
View All
Category
Human drugs
Therapeutic area
Mycoses
Active Substance
posaconazole
INN/Common name
posaconazole
Pharmacotherapeutic Classes
Antimycotics for systemic use
Status
This medicine is authorized for use in the European Union
Company
Accord Healthcare S.L.U.
Market Date
2019-07-25
2 of 5
View All
Medicine
Category
Human drugs
Therapeutic area
Candidiasis; Mycoses; Coccidioidomycosis; Aspergillosis
Active Substance
posaconazole
INN/Common name
posaconazole
Pharmacotherapeutic Classes
Antimycotics for systemic use
Status
This medicine is authorized for use in the European Union
Company
Merck Sharp and Dohme B.V
Market Date
2005-10-25

7.11 Therapeutic Uses

Mesh Heading: Antibiotics, antifungals, trypanocidal agents
National Library of Medicine, SIS; ChemIDplus Record for Posaconazole (171228-49-2). Available from, as of April 14, 2006: https://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp
MEDICATION: Antifungal; Orally activated triazole antifungal
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365
The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), was 1.96 mg . h/liter in group I and was 51% higher in group II and in group III. Increases in AUC(0-24) and maximum plasma concentration (C(max)) in groups II and III were dose related. The AUC(0-24) and C(max) values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC(0-24) and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C(max)) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.
Gubbins PO et al; Antimicrob Agents Chemother 50 (6): 1993-9 (2006)
/EXPTL:/ ... Posaconazole has demonstrated strong antifungal efficacy in Phase II and III clinical trials in immunocompromised patients with oropharyngeal and esophageal candidiasis. Posaconazole also showed promising efficacy as salvage therapy in a large Phase II study including 330 patients with invasive fungal infections intolerant to or refractory to standard therapies. ...
Groll AH et al; Expert Rev Anti Infect Ther 3 (4): 467-87 (2005)

7.12 Drug Warnings

Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies. Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for < 6 months and > or = 6 months. Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.
Raad II et al; Clin Infect Dis 42 (12): 1726-34 (2006)
The pharmacokinetic profiles, safety, and efficacies of different dosing schedules of posaconazole oral suspension in patients with possible, probable, and proven refractory invasive fungal infection (rIFI) or febrile neutropenia (FN) were evaluated in a multicenter, open-label, parallel-group study. Sixty-six patients with FN and 32 patients with rIFI were randomly assigned to one of three posaconazole regimens: 200 mg four times a day (q.i.d.) for nine doses, followed by 400 mg twice a day (b.i.d.); 400 mg q.i.d. for nine doses, followed by 600 mg b.i.d.; or 800 mg b.i.d. for five doses, followed by 800 mg once a day (q.d.). Therapy was continued for up to 6 months in patients with rIFI or until neutrophil recovery occurred in patients with FN. The 400-mg-b.i.d. dose provided the highest overall mean exposure, with 135% (P = 0.0004) and 182% (P < 0.0001) greater exposure than the 600-mg-b.i.d. and 800-mg-q.d. doses, respectively. However, exposure in allogeneic bone marrow transplant (BMT) recipients (n = 12) was 52% lower than in non-BMT patients. Treatment-related adverse events (occurring in 24% of patients) were mostly gastrointestinal in nature. Twenty-four percent of patients had adverse events leading to premature discontinuation (none were treatment related). In efficacy-evaluable patients, successful clinical response was observed in 43% with rIFI (56% of patients receiving 400 mg b.i.d., 17% receiving 600 mg b.i.d., and 50% receiving 800 mg q.d.) and 77% with FN (74% receiving 400 mg b.i.d., 78% receiving 600 mg b.i.d., and 81% receiving 800 mg q.d.). Posaconazole is well tolerated and absorbed. Divided doses of 800 mg (400 mg b.i.d.) provide the greatest posaconazole exposure.
Ullmann AJ et al; Antimicrob Agents Chemother 50 (2): 658-66 (2006)
The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. ...There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease ...Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. ...
Courtney R et al; J Clin Pharmacol 45 (2): 185-92 (2005)

8 Pharmacology and Biochemistry

8.1 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.

8.2 MeSH Pharmacological Classification

Antifungal Agents
Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)
Trypanocidal Agents
Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA. (See all compounds classified as Trypanocidal Agents.)
14-alpha Demethylase Inhibitors
Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism. (See all compounds classified as 14-alpha Demethylase Inhibitors.)

8.3 FDA Pharmacological Classification

1 of 3
FDA UNII
6TK1G07BHZ
Active Moiety
POSACONAZOLE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Azole Antifungal
Pharmacological Classes
Chemical Structure [CS] - Azoles
FDA Pharmacology Summary
Posaconazole is an Azole Antifungal.
2 of 3
Non-Proprietary Name
POSACONAZOLE
Pharmacological Classes
Azole Antifungal [EPC]; Azoles [CS]
3 of 3
Non-Proprietary Name
POSACONAZOLE DELAYED-RELEASE
Pharmacological Classes
Azole Antifungal [EPC]; Azoles [CS]

8.4 ATC Code

J02AC04

J - Antiinfectives for systemic use

J02 - Antimycotics for systemic use

J02A - Antimycotics for systemic use

J02AC - Triazole and tetrazole derivatives

J02AC04 - Posaconazole

8.5 Absorption, Distribution and Excretion

Absorption
Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
Route of Elimination
The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Volume of Distribution
1774 L
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)]

Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 hr to infinity values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 hr
Andes D et al; Antimicrob Agents Chemother 48 (1): 137-42 (2004)
The suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.
Courtney R et al; Br J Clin Pharmacol. 2004 Feb;57(2):218-22
A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1341 liters) and the terminal-phase half-life was long (range, 25 to 31 hr).
Courtney R et al; Antimicrob Agents Chemother 47 (9): 2788-95 (2003)
Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800 mg) given as a single dose (regimen A), 400 mg every 12 hours (regimen B) or 200 mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens. A total of 18 healthy men were enrolled in and completed the study. : Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 +/- 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 +/- 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 microg.h/L, with average plasma concentrations of 162, 320 and 517 microg/L for regimens A, B and C, respectively. These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.
Ezzet F et al; Clin Pharmacokinet 44 (2): 211-20 (2005)
For more Absorption, Distribution and Excretion (Complete) data for POSACONAZOLE (6 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

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.

8.7 Biological Half-Life

Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).
The i.v. terminal-phase half-lives were 7 hr in mice and rats, 15 hr in dogs, and 23 hr in monkeys. In rabbits, the oral half-life was 9 hr.
Nomeir AA et al; Antimicrob Agents Chemother 44 (3): 727-31 (2000)
Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 hr to infinity values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 hr
Andes D et al; Antimicrob Agents Chemother 48 (1): 137-42 (2004)

8.8 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.
Posaconazole is a novel lipophilic antifungal triazole that inhibits cytochrome P450-dependent 14-alpha demethylase in the biosynthetic pathway of ergosterol. Inhibition of this enzyme leads to an accumulation of toxic 14-alpha methylsterols and a depletion of ergosterol, resulting in a perturbation of the function of the fungal cell membrane and blockage of cell growth and division. ...
Groll AH et al; Expert Rev Anti Infect Ther 3 (4): 467-87 (2005)
... The primary mechanism of action of the drug was inhibition of the parasite's sterol C-14 alpha demethylase.
Urbina JA et al; Antimicrob Agents Chemother 42 (7): 1771-7 (1998)
The in vitro activity of the novel triazole antifungal agent posaconazole was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.
Sabatelli F et al; Antimicrob Agents Chemother 50 (6): 2009-15 (2006)

9 Use and Manufacturing

9.1 Uses

Mesh Heading: Antibiotics, antifungals, trypanocidal agents
National Library of Medicine, SIS; ChemIDplus Record for Posaconazole (171228-49-2). Available from, as of April 14, 2006: https://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp
MEDICATION: Antifungal
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365

Use (kg; approx.) in Germany (2009): >100

Consumption (g per capita; approx.) in Germany (2009): 0.00122

Calculated removal (%): 69.1

9.1.1 Use Classification

Human drugs -> Antimycotics for systemic use -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

A.K. Saksena et al., World Intellectual Property Organization 95 17407; US 5661151 (1995, 1997 both to Schering)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365

9.3 General Manufacturing Information

Still in FDA trials /2004/
Schering Plough; Schering-Plough Reports Key Posaconazole Data Presented At ICAAC Annual Meeting. News Relase. Oct 31, 2004. Available from, as of Apr 4, 2006: https://schering-plough.com

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Irritant
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H319 (75.5%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H351 (22.4%): Suspected of causing cancer [Warning Carcinogenicity]

H361 (98%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H372 (93.9%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H400 (95.9%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

H410 (95.9%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P264, P264+P265, P270, P273, P280, P305+P351+P338, P318, P319, P337+P317, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 49 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Eye Irrit. 2 (75.5%)

Carc. 2 (22.4%)

Repr. 2 (98%)

STOT RE 1 (93.9%)

Aquatic Acute 1 (95.9%)

Aquatic Chronic 1 (95.9%)

Reproductive toxicity - category 2

10.2 Accidental Release Measures

10.2.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11 Toxicity

11.1 Toxicological Information

11.1.1 Hepatotoxicity

Transient elevations in serum aminotransferase levels occur in 2% to 12% of patients on posaconazole. These elevations are usually mild, asymptomatic and self-limited and rarely require discontinuation of the medication. Clinically apparent hepatotoxicity is very rare. Instances of jaundice and hepatitis during posaconazole therapy are mentioned in the product label, but little information was provided on clinical details.

Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury).

11.1.2 Drug Induced Liver Injury

Compound
posaconazole
DILI Annotation
Ambiguous DILI-concern
Severity Grade
8
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the clinical use of posaconazole during breastfeeding. Because posaconazole is more than 98% bound to plasma proteins, the amount in milk is likely to be low. However, there is no published experience with posaconazole during breastfeeding, so an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

11.1.4 Interactions

Drug interactions mediated by various CYP450 are common with the currently available triazole antifungals, however ... posaconazole may have an improved and more narrow drug interaction profile (CYP3A4 only) compared with other triazoles.
Wexler D et al; Eur J Pharm Sci 21 (5): 645-53 (2004)
This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.
Courtney R et al; Antimicrob Agents Chemother 48 (3): 804-8 (2004)

11.1.5 Antidote and Emergency Treatment

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

11.1.6 Protein Binding

Posaconazole is highly protein bound (>98%), predominantly to albumin.

11.2 Ecological Information

11.2.1 Artificial Pollution Sources

Posaconazole's production and use as an antifungal medication(1) may result in its release to the environment through various waste streams(SRC).
1) O'Neil MJ, ed; The Merck Index. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1365 (2001)

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Wiley References

13.6 Chemical Co-Occurrences in Literature

13.7 Chemical-Gene Co-Occurrences in Literature

13.8 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 FDA Orange Book Patents

14.4 FDA Green Book Patents

14.5 Chemical Co-Occurrences in Patents

14.6 Chemical-Disease Co-Occurrences in Patents

14.7 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

15.4 Drug-Food Interactions

Take with food. Posaconazole suspension can also be taken with a nutritional supplement drink or carbonated beverage if a full meal cannot be consumed.

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: Drug

17.5 KEGG: USP

17.6 KEGG: ATC

17.7 KEGG: Drug Groups

17.8 KEGG : Antimicrobials

17.9 KEGG : Antimicrobials Abbreviations

17.10 KEGG: Drug Classes

17.11 WHO ATC Classification System

17.12 FDA Pharm Classes

17.13 ChemIDplus

17.14 ChEMBL Target Tree

17.15 UN GHS Classification

17.16 NORMAN Suspect List Exchange Classification

17.17 EPA DSSTox Classification

17.18 PFAS and Fluorinated Organic Compounds in PubChem

17.19 EPA Substance Registry Services Tree

17.20 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
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    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
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    https://echa.europa.eu/web/guest/legal-notice
    4-{4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-[(1H-1,2,4-triazol-1-yl)methyl]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
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    4-{4-[4-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-[(1H-1,2,4-triazol-1-yl)methyl]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 (EC: 682-747-8)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. ChEBI
  9. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
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  11. NCI Thesaurus (NCIt)
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    http://www.ebi.ac.uk/Information/termsofuse.html
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  23. EU Clinical Trials Register
  24. Hazardous Chemical Information System (HCIS), Safe Work Australia
  25. FDA Approved Animal Drug Products (Green Book)
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  26. FDA Orange Book
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  27. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.whocc.no/copyright_disclaimer/
  28. NORMAN Suspect List Exchange
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    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Posaconazole
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  29. National Drug Code (NDC) Directory
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    https://www.kegg.jp/kegg/legal.html
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    https://mona.fiehnlab.ucdavis.edu/documentation/license
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  34. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
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    https://pharos.nih.gov/about
  36. Protein Data Bank in Europe (PDBe)
  37. RCSB Protein Data Bank (RCSB PDB)
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    https://www.rcsb.org/pages/policies
  38. Springer Nature
  39. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  40. Wikidata
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    https://www.nlm.nih.gov/copyright.html
    14-alpha Demethylase Inhibitors
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  46. EPA Substance Registry Services
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    MolGenie Organic Chemistry Ontology
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  48. PATENTSCOPE (WIPO)
  49. NCBI
CONTENTS