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Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

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Abstract

Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.

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Acknowledgments

Julie Autmizguine receives support from the Training Award, Fonds Irma-Levasseur, Pediatric Department, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Jeffrey T. Guptill receives support from the American Academy of Neurology Foundation, Myasthenia Gravis Foundation of America (Clinician-Scientist Development Award) and from industry for drug development consulting (http://www.dcri.duke.edu/research/coi.jsp).

Michael Cohen-Wolkowiez receives support for research from the National Institutes of Health (NIH) (1K23HD064814), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (BARDA) (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (http://www.thrasherresearch.org), and from industry for drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp).

Daniel K. Benjamin Jr. receives support from the US Government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, UL1TR001117, and NICHD contract HHSN275201000003I) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (http://www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (http://www.dcri.duke.edu/research/coi.jsp).

Edmund V. Capparelli receives research support from the US Government (U54 HD071600-01) and consulting fees from Trius, Cerexa Pharmaceuticals, Abbott, Cempra, and Theravance.

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  1. Duke Clinical Research Institute, 2400 Pratt St, PO Box 17969, Durham, NC, 27705, USA

    Julie Autmizguine, Jeffrey T. Guptill, Michael Cohen-Wolkowiez & Daniel K. Benjamin Jr

  2. Department of Pediatric Pharmacology, University of California, 9500 Gilman Drive, La Jolla, CA, 92093-0831, USA

    Edmund V. Capparelli

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  1. Julie Autmizguine
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Autmizguine, J., Guptill, J.T., Cohen-Wolkowiez, M. et al. Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications. Drugs 74, 891–909 (2014). https://doi.org/10.1007/s40265-014-0227-3

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