Antifungal Drugs TDM: Trends and Update

Ther Drug Monit. 2021 Dec 15. doi: 10.1097/FTD.0000000000000952. Online ahead of print.

ABSTRACT

PURPOSE: The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM.

METHODS: We conducted a Pubmed search for articles during 2016-2020 using “TDM” or “pharmacokinetics” or “drug-drug-interaction” with “antifungal”, consolidated for each AF. Selection was limited to English language papers with human data on drug exposure.

RESULTS: Over 1000 papers matched the search terms. We selected 569 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The PK variability related to special populations is not specific but must be considered. AF benefit/risk ratio, drug-drug interaction (DDI) profiles and minimal inhibitory concentrations (MIC) for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetics (PBPK) modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available.

CONCLUSION: TDM appears to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

PMID:34923544 | DOI:10.1097/FTD.0000000000000952