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Pharmacodynamics of Voriconazole in Children: Further Steps Along 1
the Path to True Individualized Therapy 2
3
Luc J. Huurneman1*, Michael Neely2*, Anette Veringa1, Fernando Docobo Pérez3,4, Virginia 4 Ramos-Martin3, Wim J. Tissing5, Jan-Willem C. Alffenaar1, William Hope3 5
1University of Groningen, University Medical Center Groningen, Department of Clinical 6 Pharmacy and Pharmacology, Groningen, the Netherlands 7
2Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute 8 and the Division of Pediatric Infectious Diseases, Children's Hospital Los Angeles, University 9 of Southern California, Los Angeles, California 10
3Department of Molecular and Clinical Pharmacology, Antimicrobial Pharmacodynamics and 11 Therapeutics, University of Liverpool, Liverpool, United Kingdom. 12
4Unidad intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina 13 Preventiva. Hospital Universitario Virgen Macarena. Sevilla. Spain. 14
5University of Groningen, University Medical Center Groningen, Beatrix Children’s hospital, 15 Department of Pediatric Oncology, Groningen, the Netherlands 16
* LH and MN contributed equally to this article 17
Keywords: voriconazole, 18
Running title: PK-PD of voriconazole in children 19
Funding: Nil 20
Acknowledgements: William Hope is supported by a Clinician Scientist Fellowship from the 21 National Institute of Health Research (NIHR). Michael Neely is supported by NICHD R01 22 HD070886. 23
Conflicts of interest: JWCA received funding from Pfizer, MSD and Astellas for investigator 24 initiated studies. William Hope has received research funding from Pfizer, Gilead, Astellas 25 and F2G, and acted as a consultant and/or given talks for Pfizer, Basilea, F2G, Nordic 26 Pharma, Mayne Pharma and Pulmocide. 27
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Note. AML: acute myelogenous leukemia, ALL: acute lymphoblastic leukemia. 444 Data are presented as median (interquartile range), unless specified otherwise. 445 1 Number of patients (%). 446 a Other malignancies included non-Hodgkin lymphoma, immunodeficiency, osteosarcoma, 447 Hodgkin lymphoma, rhabdomyosarcoma. 448 b Based on the opinion of the attending physician of the Children Oncology ward at the 449 beginning of the admission. Patients classified as having possible invasive aspergillosis 450 refers to the fact that GM was initially negative when voriconazole was commenced, but later 451 became positive, at which time the diagnostic classification was upgraded to probable. 452
Figure 1: Voriconazole concentration-time profile of 12 pediatric patients (Panel A) and the 455 galactomannan-time profile (Panel B) for 12 patients who had concomitantly collected 456 galactomannan and serum voriconazole concentration data. Note: the sampling of 457 voriconazole and galactomannan were not linked. Hence, voriconazole serum concentration 458 data were available after galactomannan sampling had stopped. 459
Figure 2. The observed-predicted values after the Bayesian step for voriconazole serum 463 concentrations (left panel) and for galactomannan (right panel). The solid line is the linear 464 regression of the observed-predicted concentrations and the estimates for the intercept 465
Figure 3. Serum voriconazole concentration-time profiles (solid black line) and serum 468 galactomannan-time profiles (grey line) from the 12 children with concomitant PK and PD 469 data. The raw data for voriconazole is shown (black circles) and galactomannan (grey 470 circles). In each case, the model fit is from the Bayesian posterior estimate. Only patients 471 159 and 180 survived. 472
Figure 4. Relationship of voriconazole average daily AUC to EC50 ratio and final 476 galactomannan (i.e. last measured galactomannan) in the 12 children. Panel A: Terminal 477 Galactomannan=(AUC:EC50)/15.4 (p=0.003). Panel B: AUC:EC50 > 6 suggested a more 478 consistently lower terminal galactomannan (P=0.07). 479