72;1.51-1.95)
Phenytoin 200 mg QD PO × 10 days 200 mg (tablets) QD × 10 days† ↑ 16%
(1.16; 0.85-1.57) ↑ 16%
(1.16; 0.84-1.59)
Ritonavir 100 mg QD × 14 days 400 mg (oral suspension)
BID × 7 days ↑ 49%
(1.49; 1.04-2.15) ↑ 80%
(1.8;1.39-2.31)
Atazanavir 300 mg QD × 14 days 400 mg (oral suspension) BID × 7 days ↑ 155%
(2.55; 1.89-3.45) ↑ 268%
(3.68; 2.89-4.70)
Atazanavir/ ritonavir boosted regimen 300 mg/100 mg QD × 14 days 400 mg (oral suspension) BID × 7 days ↑ 53%
(1.53; 1.13-2.07) ↑ 146%
(2.46; 1.93-3.13)
Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.
Excretion: Posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.
Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20-66 hours).
12.4 Microbiology
Mechanism of Action:
Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.
Activity in vitro:
Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs [see Clinical Studies (14), Indications and Usage (1) and Dosage and Administration (2)]. However, correlation between the results of susceptibility tests and clinical outcome has not been established. Posaconazole interpretive criteria (breakpoints) have not been established for any fungus.
Drug Resistance:
Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconaz
