Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents
Abstract
:1. Introduction
2. Antifungals with Novel Mechanisms of Action
2.1. Manogepix
2.1.1. Mechanism of Action—Pharmacodynamics
2.1.2. Spectrum of Activity and Resistance
2.1.3. In Vivo Efficacy and Pharmacokinetics/Pharmacodynamics
2.1.4. Tolerability and Drug Interactions
2.2. Olorofim
2.2.1. Mechanism of Action—Pharmacodynamics
2.2.2. Spectrum of Activity and Mechanisms of Resistance
2.2.3. In Vivo Efficacy and Pharmacokinetics/Pharmacodynamics
2.2.4. Tolerability and Drug Interactions
2.3. Other Antifungals with Novel Mechanisms of Action
3. New Antifungals That Improve upon Current Classes and Mechanisms of Action
3.1. Ibrexafungerp
3.1.1. Mechanism of Action—Pharmacodynamics
3.1.2. Spectrum of Activity and Mechanisms of Resistance
3.1.3. In Vivo Efficacy and Pharmacokinetics/Pharmacodynamics
3.1.4. Tolerability and Drug Interactions
3.2. Rezafungin
3.2.1. Mechanism of Action—Pharmacodynamics
3.2.2. Spectrum of Activity and Mechanisms of Resistance
3.2.3. In Vivo Efficacy and Pharmacokinetics/Pharmacodynamics
3.2.4. Tolerability and Drug Interactions
3.3. Oteseconazole
3.3.1. Mechanism of Action—Pharmacodynamics
3.3.2. Spectrum of Activity and Mechanisms of Resistance
3.3.3. In Vivo Efficacy and Pharmacokinetics/Pharmacodynamics
3.3.4. Tolerability and Drug Interactions
4. New Routes of Administration
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Agent and Company Developing | Routes of Administration | PK/PD Parameter Associated with In Vivo Efficacy | Tolerability/Adverse Effects and Drug Interactions | Current Clinical Trials (Number and Phase) |
---|---|---|---|---|
Manogepix (APX001A) Pfizer | Intravenous and oral | AUC/MIC vs. yeasts (fAUC/MIC 1.35–22.54) | Well-tolerated in Phase I and II clinical studies | Candidemia/invasive candidiasis (NCT05421858, Phase III) |
AUC/MEC vs. molds (fAUC/MEC 89.39) | Drug interaction profile not yet known | |||
Olorofim (F901318) F2G | Intravenous and oral | Cmin/MIC (Cmin/MIC 3–16.5 vs. A. fumigatus) | Well-tolerated in Phase I studies with no serious adverse effects | Invasive aspergillois (NCT05101187, Phase III) |
Potential for drug interactions, as it is metabolized by CYP450 enzymes and is a weak inhibitor of CYP3A4 | Aspergillosis, lomentosporiosis, scedosporiosis, and other resistant fungi (NCT03583164, Phase II) | |||
Ibrexafungerp (SCY-078) Scynexis | Oral (Intravenous formulation under development) | AUC/MIC vs. Candida (fAUC/MIC 0.1–1.7) | Well-tolerated in Phase I and II clinical studies, and no QTc prolongations reported | Complicated vulvovaginal candidiasis (NCT05399641, Phase III) |
Invasive pulmonary aspergillosis (NCT03672292, Phase III) | ||||
AUC/MIC Possibly AUC/MEC vs. Aspergillus | Potential for drug interactions, as it is metabolized by CYP3A4 and is also an inhibitor of CYP2C8 and 3A4 | Candida auris candidiasis (NCT03363841, Phase III) | ||
Invasive mycoses in those who are refractory to or intolerant of other therapies (NCT03059992, Phase III) | ||||
Rezafungin (CD101) Cidara | Intravenous | AUC/MIC vs. Candida (fAUC/MIC 0.07–11.65) | Well-tolerated in Phase I and II clinical studies; some infusion-related reactions with higher doses | Antifungal prophylaxis in adults undergoing allogeneic stem cell transplantation (NCT04368559, Phase III) |
AUC/MEC and Cmax/MEC vs. Aspergillus | Low potential for drug interactions | |||
Oteseconazole (VT-1161) Mycovia | Oral | Undefined, but most likely AUC/MIC (similar to triazoles) | Well-tolerated in Phase I and II clinical studies with mild-to-moderate adverse effects | Recurrent vulvovaginal candidiasis (NCT03562156 and NCT033561701, Phase III—Completed) |
Drug interactions not observed with agents metabolized by CYP3A4 or p-glycoprotein |
Antifungal | Manogepix | Olorofim | Ibrexafungerp | Rezafungin | Oteseconazole |
---|---|---|---|---|---|
Yeasts | |||||
C. albicans | + | − | + | + | + |
C. auris | + | − | + | + | + |
C. glabrata | + | − | + | + | + |
C. krusei | − | − | + | + | + |
C. parapsilosis | + | − | + | + | + |
C. tropicalis | + | − | + | + | + |
C. gattii | + | − | − | − | + |
C. neoformans | + | − | − | − | + |
Rhodotorula | + | − | − | − | |
Trichosporon | +/− | − | − | − | |
Aspergillus | |||||
A. flavus | + | + | + | + | − |
A. fumigatus | + | + | + | + | − |
A. niger | + | + | + | + | − |
A. terreus | + | + | + | + | − |
Fusarium | |||||
F. oxysporum | + | +/− | − | ||
F. solani | + | − | − | ||
Scedosporium | |||||
Scedosporium | + | + | − | ||
L. prolificans | + | + | − | ||
Mucorales | |||||
Mucor | − | − | − | − | |
Rhizopus | +/− | − | − | − | +/− |
Other Mucorales | − | − | − | − | |
Endemic Fungi | |||||
Blastomyces | + | + | + | ||
Coccidioides | + | + | + | + | |
Histoplasma | + | + | + | ||
Dermatophytes | |||||
Trichophyton | + | + |
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Wiederhold, N.P. Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents. J. Fungi 2022, 8, 857. https://doi.org/10.3390/jof8080857
Wiederhold NP. Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents. Journal of Fungi. 2022; 8(8):857. https://doi.org/10.3390/jof8080857
Chicago/Turabian StyleWiederhold, Nathan P. 2022. "Pharmacodynamics, Mechanisms of Action and Resistance, and Spectrum of Activity of New Antifungal Agents" Journal of Fungi 8, no. 8: 857. https://doi.org/10.3390/jof8080857