TY - JOUR
T1 - Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients
T2 - a multicentre, prospective, cluster randomised, crossover clinical trial
AU - Veringa, Anette
AU - Brüggemann, Roger J.
AU - Span, Lambert F. R.
AU - Biemond, Bart J.
AU - de Boer, Mark G. J.
AU - van den Heuvel, Edwin R.
AU - Klein, Saskia K.
AU - Kraemer, Doris
AU - Minnema, Monique C.
AU - Prakken, Niek H. J.
AU - Rijnders, Bart J. A.
AU - Swen, Jesse J.
AU - Verweij, Paul E.
AU - Wondergem, Mariëlle J.
AU - Ypma, Paula F.
AU - Blijlevens, Nicole
AU - Kosterink, Jos G. W.
AU - van der Werf, Tjip S.
AU - voriconazole ZonMw Study Group
AU - Alffenaar, Jan-Willem C.
N1 - Funding Information: The authors would like to acknowledge the other members of the ZonMw Study Group who provided critical review of the taxonomy, but are not responsible for the content of this article: Jan P. Arends; Imke Bartelink; David M. Burger; Yuma A. Bijleveld; Simon M.G.J. Daenen; Nielka P. van Erp; Jan den Hartigh; Mirte M. Malingré; Erik M. van Maarseveen ✝; Ron A.A. Mathôt; Tahar van der Straaten; Karin M. Vermeulen; Bob Wilffert ✝; Abraham J. Wilhelm; and Marjolijn J.P van Wanrooy. They also thank all investigators, trial teams and patients for their participation in the trial. This work was supported by the Netherlands Organization for Health Research and Development [grant no. 170995005]. This funding source had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publication. This research was conducted in accordance with the Declaration of Helsinki and national and institutional standards. The trial protocol was approved by the institutional review board of the University Medical Centre Groningen for all Dutch participating centres (registration no. 2009.027) and by the Bundesinstitut für Arzneimittel und Medizinprodukte for the Oldenburg Clinic in Germany. Additionally, all Dutch centres had a local feasibility assessment. Written informed consent was obtained from all patients. This study was registered at ClinicalTrials.gov (NCT00893555). Funding Information: This work was supported by the Netherlands Organization for Health Research and Development [grant no. 170995005 ]. This funding source had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publication. Publisher Copyright: © 2023 The Authors
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. Methods: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1–6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.
AB - Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. Methods: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1–6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.
KW - Haematological malignancy
KW - Invasive fungal infection
KW - Therapeutic drug monitoring
KW - Voriconazole
UR - http://www.scopus.com/inward/record.url?scp=85147271041&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ijantimicag.2023.106711
DO - https://doi.org/10.1016/j.ijantimicag.2023.106711
M3 - Article
C2 - 36642232
SN - 0924-8579
VL - 61
SP - 106711
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
IS - 2
M1 - 106711
ER -