title: Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy.
abstract: 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.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Huurneman
authors.affiliation: Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute, and Division of Pediatric Infectious Diseases, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Anette
authors.initials: A
authors.lastname: Veringa
authors.affiliation: Department of Molecular and Clinical Pharmacology, Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom Unidad Intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Docobo Pérez
authors.affiliation: Department of Molecular and Clinical Pharmacology, Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ramos-Martin
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Oncology, Groningen, the Netherlands.
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Tissing
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
authors.affiliation: Department of Molecular and Clinical Pharmacology, Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Hope
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001228:Aspergillosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D016903:Drug Monitoring; D005260:Female; D062610:Fungal Polysaccharides / Q000032:analysis*; D005690:Galactose / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008351:Mannans / Q000032:analysis*; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D057285:Precision Medicine; D065819:Voriconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers; D062610:Fungal Polysaccharides; D008351:Mannans; C012990:galactomannan; D065819:Voriconazole; D005690:Galactose
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