Posaconazole Dr. Reddy's Mechanism of Action

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives. ATC code: J02AC04.
Pharmacology: Pharmacodynamics: Mechanism of action: Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.
Pharmacokinetics: 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 (see Dosage & Administration and as follows on recommended dose regimens).
Absorption: Posaconazole tablets are absorbed with a median Tmax of 4 to 5 hours and exhibits dose proportional pharmacokinetics after single and multiple dosing up to 300 mg.
Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy volunteers, the AUC0-72 hours and Cmax were higher compared to administration under fasted condition (51 % and 16 % for AUC0-72 hours and Cmax respectively).
Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients. The reason for this time dependency is not completely understood.
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 patients.
Posaconazole 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 after administration of the tablets, is slowly eliminated with a mean half-life (t½) of 29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. 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 plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).
Pharmacokinetics in special populations: Children (< 18 years): There is no paediatric experience with posaconazole tablets.
The pharmacokinetics of posaconazole oral suspension have been evaluated in paediatric patients. 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 paediatric patients less than 8 years of age. Similarly, in the prophylaxis data, the mean steady-state posaconazole average concentration (Cav) was comparable among adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years of age).
Gender: The pharmacokinetics of posaconazole tablets are comparable in men and women.
Elderly: The pharmacokinetics of posaconazole tablets are comparable in young and elderly patients. No overall differences in safety were observed between geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
Race: There is insufficient data among different races with posaconazole tablets.
There was a slight decrease (16 %) in the AUC and Cmax 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 data 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, in particular those receiving posaconazole after HSCT, who have 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 (Clcr ≥ 20 mL/min/1.73 m²) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In patients with severe renal impairment (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.
Similar recommendations apply to posaconazole tablets; however, there are no data with use of the posaconazole tablets.
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, 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.
Similar recommendations apply to posaconazole tablets; however, there are no data with use of the posaconazole tablets.
Microbiology: Posaconazole has been shown 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.