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Randomized Controlled Trial
. 2023 Feb;61(2):106711.
doi: 10.1016/j.ijantimicag.2023.106711. Epub 2023 Jan 13.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial

Anette Veringa  1 , Roger J Brüggemann  2 , Lambert F R Span  3 , Bart J Biemond  4 , Mark G J de Boer  5 , Edwin R van den Heuvel  6 , Saskia K Klein  7 , Doris Kraemer  8 , Monique C Minnema  9 , Niek H J Prakken  10 , Bart J A Rijnders  11 , Jesse J Swen  12 , Paul E Verweij  13 , Mariëlle J Wondergem  14 , Paula F Ypma  15 , Nicole Blijlevens  16 , Jos G W Kosterink  17 , Tjip S van der Werf  18 , Jan-Willem C Alffenaar  19 ; Voriconazole ZonMw Study Group
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Free article
Randomized Controlled Trial

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial

Anette Veringa et al. Int J Antimicrob Agents. 2023 Feb.
Free article

Abstract

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.

Keywords: Haematological malignancy; Invasive fungal infection; Therapeutic drug monitoring; Voriconazole.

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Conflict of interest statement

Competing interests R.J. Bruggeman has received fees for consulting from Gilead, F2G and Amplyx and has received research grants and given lectures for Gilead, Pfizer, Merck and Astellas. All contracts were with Radboudumc and all payments were with Radboudumc. B.J. Biemond has received research support of Sanquin, Global Blood Therapeutics and Novartis. B.J.A. Rijnders reports grants from Gilead Sciences and personal fees from F2G, outside the submitted work. J.J. Swen reports personal fees from Roche, outside the submitted work. P.E. Verweij reports grants from MSD, Gilead Sciences, F2G and Pfizer and non-financial support from IMMY, outside the submitted work. J.W.C. Alffenaar reports other financial support from Pfizer, MSD and Gilead and grants from MSD, outside the submitted work. All other authors declare no competing interests.

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