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Published on: March 17, 2023
Formulation Strategies to Overcome Amphotericin B Induced Toxicity
Sanat Kumar Dash1, Derajram Benival2, Anil B Jindal1
1Department of Pharmacy, Birla Institute of Technology and Science Pilani (BITS Pilani), Pilani Campus, Pilani, Rajasthan 333031, India.
Abstract:
Fungal infection poses a major global threat to public health because of its wide prevalence, severe mortality rate, challenges involved in diagnosis and treatment, and the emergence of drug-resistant fungal strains. Millions of people are getting affected by fungal infection, and around 3.8 million people face death per year due to fungal infection, as per the latest report. The polyene antibiotic AmB has an extensive record of use as a therapeutic moiety against systemic fungal infection and leishmaniasis since 1960. AmB has broad-spectrum fungistatic and fungicidal activity. AmB exerts its therapeutic activity at the cellular level by binding to fungal sterol and forming hydrophilic pores, releasing essential cellular components and ions into the extracellular fluid, leading to cell death. Despite using AmB as an antifungal and antileishmanial at a broad scale, its clinical use is limited due to drug-induced nephrotoxicity resulting from binding the aggregated form of the drug to mammalian sterol. To mitigate AmB-induced toxicity and to get better anti-fungal therapeutic outcomes, researchers have developed nanoformulations, self-assembled formulations, prodrugs, cholesterol- and albumin-based AmB formulations, AmB-mAb combination therapy, and AmB cochleates. These formulations have helped to reduce toxicity to a certain extent by controlling the aggregation state of AmB, providing sustained drug release, and altering the physicochemical and pharmacokinetic parameters of AmB. Although the preclinical outcome of AmB formulations is quite satisfactory, its parallel result at the clinical level is insignificant. However, the safety and efficacy of AmB therapy can be improved at the clinical stage by continuous investigation and collaboration among researchers, clinicians, and pharmaceutical companies.
Insights
Fungal infections are a global health crisis. New formulations of Amphotericin B (AmB) aim to reduce its toxicity and improve antifungal treatment outcomes, though clinical success remains limited.
Area of Science:
- Mycology and Infectious Diseases
- Pharmacology and Drug Development
- Biotechnology
Background:
- Fungal infections represent a significant global health burden, characterized by high prevalence, mortality, diagnostic challenges, and increasing drug resistance.
- Amphotericin B (AmB), a polyene antibiotic used since 1960, exhibits broad-spectrum antifungal and antileishmanial activity by disrupting fungal cell membranes.
- Clinical application of AmB is hampered by severe nephrotoxicity, primarily due to its binding to mammalian sterols.
Purpose of the Study:
- To review strategies for mitigating Amphotericin B-induced toxicity.
- To evaluate the efficacy of novel AmB formulations in improving antifungal therapeutic outcomes.
- To discuss the translational gap between preclinical success and clinical performance of AmB formulations.
Main Methods:
- Review of literature on Amphotericin B formulations, including nanoformulations, self-assembled systems, prodrugs, and combination therapies.
- Analysis of studies investigating AmB's mechanism of action and toxicity pathways.
- Assessment of preclinical and clinical data for various AmB delivery systems.
Main Results:
- Various AmB formulations (nanoformulations, prodrugs, etc.) have shown promise in preclinical studies by reducing toxicity and improving drug delivery.
- These formulations aim to control AmB aggregation, enable sustained release, and modify pharmacokinetic profiles.
- Despite promising preclinical results, the clinical efficacy and safety improvements of these advanced AmB formulations have been largely insignificant.
Conclusions:
- Novel AmB formulations offer potential for enhanced antifungal therapy by reducing toxicity.
- Bridging the gap between preclinical promise and clinical reality requires further research and interdisciplinary collaboration.
- Optimizing Amphotericin B therapy at the clinical stage necessitates continued investigation and partnerships between researchers, clinicians, and industry.
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