Noxafil Mechanism of Action

Pharmacotherapeutic Group: Anti-infective for Systemic Use, Triazole derivative. J02AC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis.
Pharmacokinetics: General Introduction: Posaconazole tablets were designated to limit release at low pH of the stomach.
The general pharmacokinetic findings across the clinical program in both healthy volunteers and patients were consistent, in that posaconazole was slowly absorbed and slowly eliminated with an extensive volume of distribution. Exposure following multiple administration of posaconazole tablets (200 or 300 mg) QD was 1.3 times higher in healthy volunteers than in patients.
The exposure to posaconazole following administration of 400 mg oral suspension twice a day was ~3 times higher in healthy volunteers than in patients, without additional safety findings at the higher concentrations.
Absorption: Posaconazole tablets are absorbed with a median t_max of 4 to 5 hours and exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg.
The absolute availability of the oral tablet is approximately 54%.
Posaconazole tablets can be given once daily after a BID dosing on Day 1.
Posaconazole oral suspension is absorbed with a median t_max of 3 hours (patients) and 5 hours (healthy volunteers). The pharmacokinetics of posaconazole oral suspension are linear following single and multiple dose administration of up to 800 mg. No further increases in exposure were observed when oral suspension doses above 800 mg daily were administered to patients and healthy volunteers. There is no effect of altered pH on the absorption of posaconazole oral suspension.
Dividing the total posaconazole oral suspension daily dose (800 mg) as 400 mg twice a day results in a 184% higher exposure relative to once-a-day administration in patients.
Effect of food on oral absorption in healthy volunteers: Posaconazole tablets can be taken without regard to food.
The AUC of posaconazole oral suspension is about 2.6 times greater when administered with a nonfat 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 oral suspension should be administered with food or a nutritional supplement.
Distribution: Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L (42%), ranging between 294-583 L among the studies in healthy volunteers.
Posaconazole oral suspension has a large apparent volume of distribution (1,774 L) suggesting extensive penetration into the peripheral tissues.
Posaconazole is highly protein bound (>98.0 %), predominantly to serum albumin.
Metabolism: 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 feces account for approximately 17% of the administered radiolabeled dose.
Excretion: Posaconazole is predominantly eliminated in the feces (77% of the radiolabeled dose) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabeled dose excreted in urine (<0.2% of the radiolabeled dose is parent drug).
Posaconazole tablet is eliminated with a mean half-life (t½) ranging between 26 and 31 hours and a mean apparent clearance ranging from 7.5 to 11 L/hr.
Posaconazole oral suspension is slowly eliminated with a mean half-life (t_½) of 35 hours (range 20 to 66 hours) and apparent total body clearance (Cl/F) of 32 L/hr. Steady-state is attained following 7 to 10 days of multiple-dose administration.
Special Populations: Pediatric: Use of posaconazole tablet in patients 13 to 17 years of age is supported by evidence from adequate and well-controlled studies of posaconazole oral suspension.
Following administration of 800 mg per day of posaconazole oral suspension 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). No pharmacokinetic data are available from pediatric patients less than 8 years of age. 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 pediatric 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 Cavg between 500 ng/mL-2500 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. No adjustment in the dosage of Noxafil is necessary based on gender.
Geriatric: Of the 230 patients treated with posaconazole tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
An increase in C_max (26%) and AUC (29%) was observed in elderly subjects (24 subjects ≥ 65 years of age) receiving the posaconazole oral suspension relative to younger subjects (24 subjects 18-45 years of age). However, in a population pharmacokinetic analysis (Study 1899) age did not influence the pharmacokinetics of posaconazole oral suspension. Further, in clinical efficacy trials, the safety profile of posaconazole oral suspension between the young and elderly patients was similar. Therefore, no dose adjustment is required for age.
Race: There is insufficient data among different races with posaconazole tablets.
Results from a multiple dose study in healthy volunteers (n = 56) indicated that there was only a slight decrease (16%) in the AUC and C_max of posaconazole oral suspension in Black subjects relative to Caucasian subjects, therefore, no dose adjustment for race is required.
Weight: Pharmacokinetic modeling for posaconazole 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.
Renal insufficiency: Following single-dose administration, there was no effect of mild and moderate renal insufficiency (n=18, Cl_cr ≥ 20 mL/min/1.73 m²) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n=6, Cl_cr < 20 mL/min/1.73 m²), the exposure of posaconazole was highly variable (96% CV) compared to the exposure in the other renal groups (<40% CV). However, as posaconazole is not significantly renally eliminated, an effect of severe renal insufficiency on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by hemodialysis. Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with posaconazole tablets.
Hepatic insufficiency: In a small number of subjects (n=12) studied with hepatic insufficiency (Child-Pugh class A, B or C), C_max values generally decreased with the severity of hepatic dysfunction (545, 414 and 347 ng/mL for the mild, moderate, and severe groups, respectively), even though the C_max values (mean 508 ng/mL) for the normal subjects were consistent with previous trials in healthy volunteers. In addition, an increase in half-life was also associated with a decrease in hepatic function (26.6, 35.3, and 46.1 hours for the mild, moderate, and severe groups, respectively), as all groups had longer half-life values than subjects with normal hepatic function (22.1 hours). Due to the limited pharmacokinetic data in patients with hepatic insufficiency, no recommendation for dose adjustment can be made.
Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with posaconazole tablets.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis: 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.
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.
Microbiology: Posaconazole has been shown in vitro and in clinical infections to be active against the following micro-organisms: Aspergillus species (A. fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus, A. ochraceus), Candida species (C. albicans, C. glabrata, C. krusei, C. parapsilosis), Cryptococcus neoformans, Coccidioides immitis, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii and species of Alternaria, Exophiala, Fusarium, Ramichloridium, Rhizomucor, Mucor, and Rhizopus.
Posaconazole also exhibits in vitro activity against the following yeasts and moulds: Candida dubliniensis, C. famata, C. guilliermondii, C. lusitaniae, C. kefyr, C. rugosa, C. tropicalis, C. zeylanoides, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis, Cryptococcus laurentii, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowia lipolytica, species of Pichia, and Trichosporon, Aspergillus sydowii, Bjerkandera adusta, Blastomyces dermatitidis, Epidermophyton floccosum, Paracoccidioides brasiliensis, Scedosporium apiospermum, Sporothrix schenckii, Wangiella dermatitidis and species of Absidia, Apophysomyces, Bipolaris, Curvularia, Microsporum, Paecilomyces, Penicillium, and Trichophyton. However, the safety and effectiveness of posaconazole in treating clinical infections due to these microorganisms have not been established in clinical trials.
Posaconazole 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 and Rhizomucor).
In vitro posaconazole exhibited fungicidal activity against species of: Aspergillus; dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, Coccidioides immitis); some species of Candida.
In animal infection models posaconazole 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.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Drug Resistance: C. albicans strains resistant to posaconazole could not be generated in the laboratory; spontaneous laboratory Aspergillus fumigatus mutants exhibiting a decrease in susceptibility to posaconazole arose at a frequency of 1x10^-8 to 1x10^-9. Clinical isolates of Candida albicans and Aspergillus fumigatus exhibiting significant decreases in posaconazole susceptibility are rare. In those rare instances where decreased susceptibility was noted, there was no clear correlation between decreased susceptibility and clinical failure. Clinical success has been observed in patients infected with organisms resistant to other azoles; consistent with these observations posaconazole was active in vitro against many Aspergillus and Candida strains that developed resistance to other azoles and/or amphotericin B. Breakpoints for posaconazole have not been established for any fungi.
Antifungal medicinal product combinations: When combinations of posaconazole with either amphotericin B or caspofungin were tested in vitro and in vivo there was little or no antagonism and in some instances there was an additive effect. The clinical significance of these results is unknown.