Pharmacokinetics–pharmacodynamics of antifungal agents in the central nervous system

ABSTRACT

Introduction: Mortality from invasive fungal disease involving the central nervous system (CNS) is excessive. Achieving therapeutic drug concentrations at the site of infection within the CNS is always difficult and its evaluation is complex due to anatomical barriers and variable pathophysiological lesions.

Areas covered: This review provides an updated summary of the CNS PK of antifungal therapies. It considers factors that influence the success of antifungal regimens for CNS infection as well as preclinical and clinical data that quantify antifungal pharmacokinetics (PK) in the CNS. Furthermore, it presents state-of-the-art technologies to enhance the clinical use of existing antifungal drugs, and introduces novel antifungal drugs in development.

Expert opinion: The antifungal drugs currently available are either suboptimal, or are being used suboptimally, for CNS disease. Therapeutic drug monitoring is mandatory to enhance their effectiveness. Novel drugs in development may offer more efficacious options. In all cases, contemporary technologies to assess CNS PK offer the opportunity to enhance our understanding and use of antifungal drugs for CNS fungal disease.

KEYWORDS:

• Antifungal
• central nervous system
• cerebrospinal fluid
• brain
• pharmacokinetics
• distribution

Article highlights

• The pathophysiology of fungal infections of the CNS is varied and impacts the pharmacokinetic-pharmacodynamic targets of antifungal drugs for these infections.

• Physicochemical properties of drugs influence their propensity to reach therapeutic CNS concentrations.

• Antifungal pharmacokinetic variability is significant, and heightened in the context of CNS penetration.

• Several new antifungal agents are in development and may be of clinical utility for CNS infections.

• Advancing technologies enhance our ability to quantify and evaluate CNS pharmacokinetics.

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Declaration of interest

W Hope holds or has recently held research grants with F2G, AiCuris, Astellas Pharma, Spero Therapeutics, Matinas Biosciences, Antabio, Amplyx, Allecra and Pfizer. W Hope holds awards from the National Institutes of Health, Medical Research Council, National Institute of Health Research, and the European Commission (FP7 and IMI). W Hope has received personal fees in his capacity as a consultant for F2G, Amplyx, Ausperix, Spero Therapeutics, Medicines Company, Gilead and Basilea. W Hope is Medical Guideline Director for the European Society of Clinical Microbiology and Infectious Diseases, and an Ordinary Council Member for the British Society of Antimicrobial Chemotherapy. 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

K Stott receives funding from the Wellcome Trust [grant number 203919/Z/16/Z].