Antimycotics for systemic use, Triazole derivatives. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of action:
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.
Combination with other antifungal agents:
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or the other therapies; however, there is currently no clinical evidence that combination therapy will provide an added benefit.
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus
infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus
(see Dosage & Administration and Pharmacokinetics as follows on recommended dose regimens and the effects of food on absorption).
Invasive aspergillosis: Oral posaconazole 800 mg/day in divided doses was evaluated for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-comparative salvage therapy trial. Clinical outcomes were compared with those in an external control group derived from a retrospective review of medical records. The external control group included 86 patients treated with available therapy (as previously mentioned) mostly at the same time and at the same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were considered to be refractory to prior therapy in both the posaconazole group (88%) and in the external control group (79%).
As shown in Table 1, a successful response (complete or partial resolution) at the end of treatment was seen in 42% of posaconazole-treated patients compared to 26% of the external group. However, this was not a prospective, randomised controlled study and so all comparisons with the external control group should be viewed with caution. (See Table 1.)
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Other Serious Fungal Pathogens: Posaconazole has been shown to be effective against the following additional pathogens when other therapy had been ineffective or when the patient had developed intolerance of the prior therapy: Zygomycosis:
Successful responses to posaconazole therapy were noted in 7/13 (54%) of patients with zygomycete infections. Sites of infection included the sinuses, lung, and skin. Organisms included Rhizopus, Mucor and Rhizomucor. Most of the patients had underlying haematological malignancies, half of which required a bone marrow transplant. Half of the patients were enrolled with intolerance to previous therapy and the other half as a result of disease that was refractory to prior therapy. Three patients were noted to have disseminated disease, one of which had a successful outcome after failing amphotericin B therapy.
spp.: 11 of 24 (46%) patients who had proven or probable fusariosis were successfully treated with posaconazole 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, seven patients were classed as responders.
Chromoblastomycosis/Mycetoma: 9 of 11 (82%) patients were successfully treated with posaconazole 800 mg/day in divided doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis due to Fonsecaea pedrosoi
and 4 had mycetoma, mostly due to Madurella
Coccidioidomycosis: 11 of 16 (69%) patients were successfully treated (at the end of treatment complete or partial resolution of signs and symptoms present at baseline) with posaconazole 800 mg/day in divided doses for a median of 296 days and up to 460 days.
Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC): A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (most patients studied had C. albicans
isolated at baseline). The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).
The clinical response rates from the previous study are shown in Table 2.
Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as well as 4 weeks after the end of treatment. (See Table 2.)
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Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899): Two randomised, controlled prophylaxis studies were conducted among patients at high risk for developing invasive fungal infections.
Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority (377/600, [63%]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5%]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for fluconazole.
Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post-randomization. New diagnosis of acute myelogenous leukemia was the most common underlying condition (435/602, [72%]). The mean duration of therapy was 29 days for posaconazole and 25 days for fluconazole/itraconazole.
In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 3 and 4 for results from both studies. There were fewer breakthrough Aspergillus
infections in patients receiving posaconazole prophylaxis when compared to control patients. (See Tables 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed [POS 49/304 (16%) vs. FLU/ITZ 67/298 (22%) p=0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P=0.0354) as well as IFI-related deaths (P=0.0209).
In Study 316, overall mortality was similar (POS, 25%; FLU, 28%); however, the proportion of IFI-related deaths was significantly lower in the POS group (4/301) compared with the FLU group (12/299; P=0.0413).
Use in paediatric patients:
Sixteen patients 8-17 years of age were treated with 800 mg/day in a study for invasive fungal infections (Study 0041). Based on the available data in 16 of these paediatric patients, the safety profile appears to be similar to patients ≥18 years of age.
Additionally, twelve patients 13-17 years of age received 600 mg/day for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be similar to patients ≥18 years of age. In a study (Study 03579) of 136 neutropenic paediatric patients 11 months-17 years treated with posaconazole oral suspension at doses up to 18 mg/kg/day divided TID, approximately 50% met the prespecified target (Day 7 Cav between 500 ng/mL-2,500 ng/mL) (see Pharmacokinetics as follows).
Safety and efficacy in paediatric patients below the age of 18 years have not been established.
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during administration of posaconazole (400 mg twice daily with high fat meals) from 173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the mean QTc (Fridericia) interval from baseline were observed.
Posaconazole is absorbed with a median tmax
of 3 hours (fed patients). The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg when taken with a high fat meal. No further increases in exposure were observed when doses above 800 mg daily were administered to patients and healthy volunteers. In the fasting state, AUC increased less than in proportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the total daily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown to increase posaconazole exposure by 58% over 48 hours.
Effect of food on oral absorption in healthy volunteers:
The AUC of posaconazole is about 2.6 times greater when administered with a non-fat meal or nutritional supplement (14 grams fat) and 4 times greater when administered with a high-fat meal (~50 grams fat) relative to the fasted state. Posaconazole should be administered with food or a nutritional supplement (see Dosage & Administration).
Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution (1,774 litres) and is highly protein bound (>98%), predominantly to serum albumin.
Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites observed. The excreted metabolites in urine and faeces account for approximately 17% of the administered radiolabelled dose.
Posaconazole is slowly eliminated with a mean half-life (t½
) of 35 hours (range 20 to 66 hours). After administration of 14
C-posaconazole, radioactivity was predominantly recovered in the faeces (77% of the radiolabelled dose) with the major component being parent compound (66% of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabelled dose excreted in urine (<0.2% of the radiolabelled dose is parent compound). Steady-state is attained following 7 to 10 days of multiple-dose administration.
Pharmacokinetics in special populations:
Children (<18 years): Following administration of 800 mg per day of posaconazole as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8-17 years of age (776 ng/ml) were similar to concentrations from 194 patients 18-64 years of age (817 ng/ml). Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥18 years of age). In a study of 136 neutropenic paediatric patients 11 months-17 years treated with posaconazole oral suspension at doses up to 18 mg/kg/day divided TID, approximately 50% met the prespecified target (Day 7 Cav between 500 ng/mL-2,500 ng/mL). In general, exposures tended to be higher in the older patients (7 to <18 years) than in younger patients (2 to <7 years).
Gender: The pharmacokinetics of posaconazole are comparable in men and women.
Elderly (≥65 years): An increase in Cmax
(26%) and AUC (29%) was observed in elderly subjects (24 subjects ≥65 years of age) relative to younger subjects (24 subjects 18-45 years of age). However, in clinical efficacy trials, the safety profile of posaconazole between the young and elderly patients was similar.
Race: There was a slight decrease (16%) in the AUC and Cmax
of posaconazole in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.
Weight: Pharmacokinetic modeling with an oral tablet formulation suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg. Patients with a low body weight (<60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.
Renal impairment: Following single-dose administration, there was no effect of mild and moderate renal impairment (n=18, Clcr
≥20 ml/min/1.73 m2
) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Clcr
<20 ml/min/1.73 m2
), the AUC of posaconazole was highly variable [>96% CV (coefficient of variance)] compared to other renal groups [<40% CV]. However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.
Hepatic impairment: After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that there is a larger increase in unbound posaconazole exposure than the observed 60% increase in total AUC. The elimination half-life (t½
) was prolonged from approximately 27 hours up to ~43 hours in respective groups. No dose adjustment is recommended for patients with mild to severe hepatic impairment but caution is advised due to the potential for higher plasma exposure.
Toxicology: Preclinical safety data:
As observed with other azole antifungal agents, effects related to inhibition of steroid hormone synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.
Neuronal phospholipidosis occurred in dogs dosed for ≥3 months at lower systemic exposures than those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed on the central or peripheral nervous systems at systemic exposures greater than those achieved therapeutically.
Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 2-year study in rats. These findings are not necessarily indicative of a potential for functional changes in humans.
No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety pharmacology study in monkeys at systemic exposures 4.6-fold greater than the exposures obtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, respectively, than those achieved with therapeutic doses.
Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were considered to be due to a treatment-related effect on steroidogenesis.
Posaconazole was not genotoxic in in vitro
and in vivo
studies. Carcinogenicity studies did not reveal special hazards for humans.
Posaconazole has been shown in vitro
to be active against the following microorganisms: Aspergillus
species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus
species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis
), Coccidioides immitis, Fonsecaea pedrosoi
, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus
. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor
, and Rhizopus
, however the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents.
NOXAFIL exhibits broad-spectrum antifungal activity against some yeasts and moulds not generally responsive to azoles, or resistant to other azoles: species of Candida
(including C. albicans
isolates resistant to fluconazole, voriconazole and itraconazole; C. krusei
and C. glabrata
which are inherently less susceptible to fluconazole; C. lusitaniae
which is inherently less susceptible to amphotericin B); Aspergillus
(including isolates resistant to fluconazole, voriconazole, itraconazole and amphotericin B); organisms not previously regarded as being susceptible to azoles such as the zygomycetes (e.g. species of Absidia, Mucor, Rhizopus
NOXAFIL exhibited fungicidal activity against species of: Aspergillus
; dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, Coccidioides immitis
ome species of Candida
In animal infection models NOXAFIL was active against a wide variety of fungal infections caused by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory concentration and efficacy.
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.