Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients

ABSTRACT

Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined exposure–response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.

Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.

Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure–response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.

KEYWORDS:

• Antifungal agent
• antifungal dose modification
• flucytosine
• invasive fungal infection
• itraconazole
• pediatrics
• pharmacodynamics
• posaconazole
• therapeutic drug monitoring
• voriconazole

Article highlights

• Therapeutic drug monitoring may be considered for an antifungal agent that has a well-defined exposure–response relationship and either a narrow therapeutic index, substantial pharmacokinetic variability, and/or potential for genetic polymorphisms to impact clearance. Other clinical scenarios include patients with altered hepatic or renal function, extremes of age or weight, patient adherence or absorption concerns, treatment of organisms with elevated minimum inhibitory concentrations, or drug–drug interactions potentially impacting antifungal serum concentrations.

• Antifungal agents that are currently recommended for routine therapeutic drug monitoring include flucytosine, itraconazole, voriconazole, and posaconazole. Considerations and rationale for therapeutic drug monitoring of each of these agents are summarized in Tables 1 and 2, respectively. Alternatively, therapeutic drug monitoring is not routinely recommended for amphotericin B, fluconazole, isavuconazole, and echinocandin agents.

• Several new antifungal agents are currently in development and may not require routine therapeutic drug monitoring given anticipated predictable pharmacokinetics.

Declaration of interest

T.J. Walsh declares receiving grants for experimental and clinical antimicrobial pharmacology and therapeutics to his institution from Allergan, Amplyx, Astellas, Lediant, Medicines Company, Merck, Scynexis, T2 Biosystems, and Tetraphase and serving as consultant to Amplyx, Astellas, Allergan, Gilead, Lediant, and Scynexis and Medicines Company.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

TJ Walsh was supported for this work by the following foundations: Henry Schueler Foundation and the Save Our Sick Kids Foundation.