Rezafungin 200mg powder for solution for infusion vials

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

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In recent years, many population pharmacokinetic (popPK) models have been developed for echinocandins to better understand the pharmacokinetics (PK) of these antifungals. This comprehensive review aimed to summarize popPK models of echinocandins (micafungin, caspofungin, anidulafungin, and rezafungin), by focusing on dosage optimization to maximize the probability of attaining the PK/PD target proposed in special populations. A search in PubMed, Embase, Web of Science, and Scopus, supplemented by the bibliography of relevant articles, was conducted from inception to March 2024, including both observational and prospective trials. A total of 1126 articles were identified, 47 of them were included in the review (22 for micafungin, 13 for caspofungin, 9 for anidulafungin, and 3 for rezafungin). A two-compartment model was more frequently used to describe the PK parameters of echinocandin (78.7% of developed models), although more complex structural models with three and four compartments have also been developed. The covariates to estimate the PK parameters such as clearance (CL) and volume of distribution (Vd) differed between models. Weight total (WT) was the most frequently reported to be a significant predictor for both parameters, especially for estimating the CL in pediatrics. The PD parameter most widely reported assessing the drug exposure–efficacy relationship was the area under the concentration–time curve to minimum inhibitory concentration (MIC) ratio (AUC0–24/MIC) with different targets proposed for each echinocandin. In certain populations such as patients that are critically ill, obese, receiving extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), or pediatric patients and/or patients with cancer or that are immunocompromised, the fixed dosing strategies recommended in the drug prescribing information may not reach the PK/PD target. For these populations, different strategies have been proposed, such as a dosing regimen based on body weight or increasing the loading and/or maintenance dose. Despite echinocandins’ favorable safety profile and predictable PK, certain groups at risk of suboptimal drug exposure can benefit from therapeutic drug monitoring (TDM) to prevent clinical failures. Numerous popPK models of echinocandins have been developed. However, an external validation of the suggested dosing regimens in conjunction with an analysis of population subgroups should be conducted before implementing a popPK model in clinical practice.

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Achieving and maintaining therapeutic drug exposures with antifungals can be challenging in special patient populations, such as those with organ dysfunction (liver or kidney) or obesity, or elderly patients, due to dose-exposure relationships and potential drug-drug interactions. Dose adjustments may be needed in these populations to maintain therapeutic efficacy and/or prevent toxicity. We reviewed specific dosing considerations for antifungals in special populations with candidaemia and/or invasive candidiasis, focusing on those relating to echinocandins (based on prescribing information), and then explored the utility of the second-generation echinocandin rezafungin in treating these populations (based on currently available data identified from a PubMed and congress abstract search). Available data showed that echinocandins may sometimes require dosing modifications for special populations with candidaemia/invasive candidiasis, primarily due to decreases in pharmacokinetic exposures. Rezafungin appears to be suitable for use in a variety of special populations without the need for dose modifications based on available data, including patients with organ dysfunction or obesity, and elderly and critically ill patients. Further research is needed in populations where rezafungin data are not available including children, people living with HIV, patients receiving extracorporeal membrane oxygenation and those with underlying neurological conditions.

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This mini-review summarizes the clinical outcomes and antifungal susceptibility results, where available, for three new antifungals, including fosmanogepix, ibrexafungerp, and rezafungin, against Candida isolates cultured from patients in clinical trials. When reported, most of the data were generated by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method or by both the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies. For fosmanogepix, we summarize the in vitro data for C. auris isolates from 9 patients and for Candida spp. cultured from 20 patients in two clinical trials. Ibrexafungerp has also been evaluated in several clinical trials. From conference proceedings, a total of 176 Candida isolates were evaluated in the FURI and CARES studies, including 18 C. auris isolates (CARES study). However, MIC data are not available for all clinical isolates. Results from the ReSTORE rezafungin phase 3 clinical study also included in vitro results against Candida spp., but no patients with C. auris infections were included. In conclusion, this mini-review summarizes insights regarding clinical outcomes and the in vitro activity of three new antifungals against Candida spp. cultured from patients in clinical trials.

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Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC50) and half enzyme maximal inhibitory concentration 50% (IC50)) and spectrum, the same target, and the same mechanisms of resistance. The selection of FKS mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.

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Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies.

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