Journal
DRUGS
Volume 74, Issue 8, Pages 891-909Publisher
ADIS INT LTD
DOI: 10.1007/s40265-014-0227-3
Keywords
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Categories
Funding
- Training Award, Fonds Irma-Levasseur, Pediatric Department, Sainte- Justine University Hospital Center, Montreal, QC, Canada
- American Academy of Neurology Foundation
- Myasthenia Gravis Foundation of America
- industry for drug development consulting
- National Institutes of Health (NIH) [1K23HD064814]
- National Center for Advancing Translational Sciences of the NIH [UL1TR001117]
- Food and Drug Administration [1U01FD004858-01]
- Biomedical Advanced Research and Development Authority (BARDA) [HHSO100201300009C]
- nonprofit organization Thrasher Research Fund
- industry for drug development in adults and children
- US Government (NICHD) [UL1TR001117, 1R01HD057956-05, 1K24HD058735-05, HHSN275201000003I]
- industry for neonatal and pediatric drug development
- US Government [U54 HD071600-01]
- Trius
- Cerexa Pharmaceuticals
- Abbott
- Cempra
- Theravance
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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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