Posaconazole

Indications

Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients aged 13 and older who are at significant risk due to severe immunocompromise. This risk is typically associated with patients who have undergone procedures such as hematopoietic stem cell transplantation (HSCT) and are experiencing graft-versus-host disease (GVHD), or in those with hematologic malignancies accompanied by prolonged neutropenia resulting from chemotherapy. Additionally, Posaconazole is prescribed for the treatment of oropharyngeal candidiasis, including cases that are resistant to itraconazole and/or fluconazole. It also serves as an alternative therapy for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are either intolerant to or have refractory responses to other antifungal agents.

Pharmacodynamics

Posaconazole is a potent antifungal agent structurally akin to itraconazole. It has been derived by substituting chlorine with fluorine in the phenyl ring and undergoing hydroxylation of its triazolone side chain, enhancing both its potency and its spectrum of activity. The drug can demonstrate either fungicidal or fungistatic effects depending on the specific fungal species and concentration levels achieved at the site of infection.

Absorption

Posaconazole demonstrates a median time to maximum concentration (Tmax) of approximately 3 to 5 hours following administration. This characteristic indicates that the drug is absorbed in a moderate timeframe post-dosing, which is an important consideration for timing in clinical settings.

Metabolism

In the systemic circulation, Posaconazole is primarily found as the parent compound. The principal metabolic pathway involves glucuronidation, resulting in glucuronide conjugates, primarily mediated by phase 2 enzymes. Notably, Posaconazole does not produce significant oxidative metabolites via the cytochrome P450 pathway. Approximately 17% of the radiolabeled dose is eliminated in the urine and feces as excreted metabolites.

Mechanism of Action

Posaconazole functions as a triazole antifungal agent by targeting and inhibiting the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungal organisms. This enzyme is crucial for the synthesis of ergosterol, an essential component of the fungal cell membrane. By binding to the heme cofactor on the enzyme, posaconazole effectively disrupts ergosterol production, leading to an accumulation of methylated sterol precursors. This disruption in sterol biosynthesis hampers fungal cell growth and ultimately induces cell death.