Posaconazole exhibits strong anti-tubercular properties. Posaconazole and amiodarone work in concert. In T. cruzi, posaconazole also has an impact on and disturbs Ca2+ homeostasis. The biosynthesis of ergosterol, which is necessary for the survival of parasites, is blocked by posaconazole. Posaconazole, with an IC50 of 14 nM and a minimal inhibitory concentration of 20 nM, clearly affects the proliferation of the epimastigote (extracellular) stages in a dose-dependent manner. Posaconazole is even more effective against the clinically significant intracellular amastigote form of the parasite. The minimal inhibitory concentration (MIC50) of posaconazole is 3 nM, while its half-life is 0.25 nM [1]. Posaconazole is significantly more effective than the other triazoles against zygomycetes and is active against isolates of Candida and Aspergillus species that show resistance to Fluconazole, Voriconazole, and Amphotericin B. [2]

When amiodarone is administered alone to infected animals, it decreases parasitemia, increases survival 60 days after infection (0% for untreated controls vs. 40% for amiodarone-treated animals), and delays the onset of parasitemia when combined with posaconazole[1].
When Posaconazole and Boost Plus are administered together during a fast, the amount of drug exposed to the patient is greater than when Posaconazole is administered alone. Food dramatically raises the bioavailability of posaconazole, especially meals with a high fat content. When posaconazole is taken with a high-fat or nonfat meal, the amount of systemic exposure to the drug increases by 4 and 2.6 times, respectively[3].
Amiodarone and posaconazole could make up a low-side-effect anti-T. cruzi treatment that works well[4].
When administered twice daily at a dose of greater than 15 mg/kg of body weight, posaconazole decreases tissue burden and increases mouse survival[5].

The parasite's epimastigote form is grown in liver infusion tryptose medium,12 with 10% fresh calf serum added, at 28°C and vigorous (120 rpm) agitation. Drugs are added to cultures at a cell density of 0.5−1.0 ×107 epimastigotes mL-1, after they are started at a density of 2×106 epimastigotes mL-1. Both direct counting with a hemocytometer and electronic particle counting are used to measure cell densities.Trypan blue exclusion is used to measure cell viability under light microscopy. As previously mentioned, amastigotes are cultivated in Vero cells kept in minimal essential medium supplemented with 1% fetal calf serum at 37°C in a humidified atmosphere (95% air−5% CO2). After two hours of infection with ten tissue culture-derived trypomastigotes per cell, nonadherent parasites are eliminated by three rounds of phosphate-buffered saline (PBS) washing. The cells are cultured for 96 hours, changing the medium every 48 hours, adding fresh medium both with and without medications. Using light microscopy, the percentage of infected cells and the number of parasites per cell are directly measured. The data are then statistically analyzed as previously mentioned.Using the GraFit program, nonlinear regression is used to calculate IC50 values. Once more using Fura-2, fluorimetric techniques are used to determine the cytoplasmic free Ca2+ concentrations in control and drug-treated extracellular epimastigotes (see previous description). Time-scan confocal microscopy is used to measure the subcellular Ca2+ levels and mitochondrial membrane potentials on individual Vero cells infected with T. cruzi amastigotes; this technique is covered in detail elsewhere. In short, Vero cells had a 72-hour heavy T infection.Cruzi amastigotes are plated onto glass coverslips measuring 22 by 40 mm and have a thickness of 0.15 mm. They are then incubated for 50 minutes at 37°C in culture medium with 10 μM cell-permeant Rhod-2 and 10 μg/mL Rhodamine-123. After this, they are rinsed and incubated with Ringer's solution, either with or without amiodarone. Rhod-2's low affinity for Ca2+ limits its fluorescence in the Ca2+-poor cytoplasm of Vero cells or amastigotes, hence under the conditions used, its fluorescence is primarily derived from intracellular Ca2+-rich compartments, such as mitochondria. A cationic dye called rhodamine-123 is unique to mitochondria and is distributed across the inner membranes in strict accordance with their membrane potential.

The murine model of acute Chagas disease is used for in vivo studies. Female NMRI-IVIC mice (20–25 g) are infected with 105 or 103 bloodstream trypomastigotes, and drug treatment is initiated 24 hours later. For 30 days in a row, treatments consist of 30 doses of posaconazole (20 mg/kg/d) or 15 doses of amiodarone (5 mg/kg every other day).Positive controls are given the anti-T. cruzi drug nifurtimox at a dose of 50 mg/kg/d for 30 days, whereas negative controls, or animals that are not given any treatment, are given just the vehicle. Every day, survival is monitored, and every week, parasitemia is assessed through direct microscopic inspection. After 60 days of observation following infection, parasitological cures are assessed using a combination of blood PCR tests, xenodiagnosis, and hemoculture.

Absorption, Distribution and Excretion
Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
1774 L
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
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.
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).
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.
For more Absorption, Distribution and Excretion (Complete) data for POSACONAZOLE (6 total), please visit the HSDB record page.

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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.

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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.
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

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).

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

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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.
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.

[1]. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J Med Chem. 2006 Feb 9;49(3):892-9.

[2]. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother. 2006 Jun;50(6):2009-15.

[3]. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother. 2006 May;50(5):1881-3. .

[4]. Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents. 2012 Jul;40(1):61-71.

[5]. In vivo activity of posaconazole against Mucor spp. in an immunosuppressed-mouse model. Antimicrob Agents Chemother. 2002 Jul;46(7):2310-2.

Therapeutic Uses
Mesh Heading: Antibiotics, antifungals, trypanocidal agents
MEDICATION: Antifungal; Orally activated triazole antifungal
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.
/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. ...

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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.
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.
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. ...

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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.

C37H42F2N8O4

700.78

700.329

C, 63.41; H, 6.04; F, 5.42; N, 15.99; O, 9.13

171228-49-2

Posaconazole-d5;1217785-83-5;Posaconazole-d4;1133712-26-1;Posaconazole hydrate;1198769-38-8

468595

White to off-white solid powder

1.4±0.1 g/cm3

850.7±75.0 °C at 760 mmHg

170-1720C

468.3±37.1 °C

0.0±0.3 mmHg at 25°C

1.658

2.25

1

11

12

51

1170

4

FC1=CC=C([C@@]2(CN3C=NC=N3)C[C@H](COC4=CC=C(N5CCN(C6=CC=C(N7C=NN([C@@H](CC)[C@H](C)O)C7=O)C=C6)CC5)C=C4)CO2)C(F)=C1

RAGOYPUPXAKGKH-XAKZXMRKSA-N

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

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

Posaconazole; Noxafil; SCH-56592; Schering 56592; Sch 56592; Schering 56592;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 18.75~100 mg/mL ( 26.76~142.69 mM )

Solubility in Formulation 1: ≥ 1.88 mg/mL (2.68 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 18.8 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.88 mg/mL (2.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 18.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.88 mg/mL (2.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 18.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 1.88 mg/mL (2.68 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)