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Métodos Terapéuticos y Terapias MTCI
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1.
Antimicrob Agents Chemother ; 60(4): 2336-42, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26833158

RESUMEN

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P= 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P= 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival.


Asunto(s)
Antifúngicos/farmacocinética , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Polisacáridos Fúngicos/análisis , Mananos/análisis , Voriconazol/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Área Bajo la Curva , Aspergilosis/sangre , Aspergilosis/microbiología , Aspergillus fumigatus/crecimiento & desarrollo , Aspergillus fumigatus/metabolismo , Biomarcadores/análisis , Niño , Preescolar , Simulación por Computador , Monitoreo de Drogas , Femenino , Galactosa/análogos & derivados , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Modelos Estadísticos , Medicina de Precisión , Voriconazol/administración & dosificación , Voriconazol/sangre
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