Recent Therapeutic Advances and Emerging Repurposing Strategies of Posaconazole: A Comprehensive Review

Globally, fungal diseases exert a considerable toll on human health, exhibiting wideranging epidemiological patterns across geographic locales. In the post-COVID era, the prevalence and risk of fungal infections have grown at an unprecedented pace, posing a colossal challenge to people with impaired immune systems owing to indiscriminate use of immunosuppressants and anti-fungal agents. In recent times, posaconazole (PCZ), a triazole with broad-spectrum activity, has emerged as a promising therapeutic option for the efficacious management of invasive fungal infections caused by Candida spp., Aspergillus spp., and Zygomycetes, with superior protection against endemic fungi such as Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis. PCZ (commercially available as Noxafil® suspension at a dose of 40 mg/ml and delayed release tablet with a daily dose of 300-600 mg) was one of the front-line therapies approved by the USFDA in 2006 for the prophylactic treatment of COVID-associated pulmonary aspergillosis or mucormycosis, especially among critically immunocompromised patients undergoing mechanical ventilation and high-dose steroid treatment for progressive pulmonary disease. In clinical settings, existing PCZ formulations (tablets/suspensions) have achieved suboptimal peak plasma drug concentrations in critically ill patients owing to poor bioavailability. Therefore, the scientific community is striving to design and fabricate novel PCZ formulations with improved pharmacokinetic performance and therapeutic efficacy compared to existing dosage forms. This comprehensive review study aims to elucidate the mechanistic corroborations on therapeutic efficacy of PCZ and its resistance, considerations in the formulation and optimization (such as drug-drug interactions, variable absorption, and potential adverse effects such as hepatotoxicity and gastrointestinal disturbances) necessitate vigilant monitoring and dose adjustments by investigating marketed products, clinical trials, patented formulations, for its enhanced pharmacokinetic performance and continued surveillance of PCZ in clinical practice.