Posaconazole

Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Microbiology

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), Candida 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.

Resistance

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.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.

The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance, have been determined by EUCAST methodology. EUCAST ECOFF values:

• Aspergillus flavus: 0.5 mg/L
• Aspergillus fumigatus: 0.25 mg/L
• Aspergillus nidulans: 0.5 mg/L
• Aspergillus niger: 0.5 mg/L
• Aspergillus terreus: 0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.

Breakpoints

EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:

• Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
• Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
• Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L

There are currently insufficient data to set clinical breakpoints for other Candida species.

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.

Pharmacokinetic/Pharmacodynamic relationships

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.

Absorption

Posaconazole is absorbed with a median t_max 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 2.6-fold.

Effect of food on oral absorption in healthy volunteers

The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily) was administered during and immediately after the consumption of a high fat meal (~50 grams fat) compared to administration before a meal, with C_max and AUC increasing by approximately 330% and 360%, respectively. The AUC of posaconazole is: 4 times greater when administered with a high-fat meal (~50 grams fat) and about 2.6 times greater when administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the fasted state.

Distribution

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.

Biotransformation

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.

Elimination

Posaconazole is slowly eliminated with a mean half-life (t_1⁄2) of 35 hours (range 20 to 66 hours). After administration of ¹⁴C-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 pre-specified 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 C_max (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 C_max of posaconazole oral suspension in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.

Weight

Pharmacokinetic modelling 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 of posaconazole oral suspension, there was no effect of mild and moderate renal impairment (n=18, Cl_cr ≥20 mL/min/1.73 m²) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl_cr <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 (t_½) 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.

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 concentrations 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 the human 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.