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; Roger J Brüggemann; Lambert F R Span; Bart J Biemond; Mark G J de Boer; Edwin R van den Heuvel; Saskia K Klein; Doris Kraemer; Monique C Minnema; Niek H J Prakken; Bart J A Rijnders; Jesse J Swen; Paul E Verweij; Mariëlle J Wondergem; Paula F Ypma; Nicole Blijlevens; Jos G W Kosterink; Tjip S van der Werf; Jan-Willem C Alffenaar; Voriconazole ZonMw Study Group

doi:10.1016/j.ijantimicag.2023.106711

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

Int J Antimicrob Agents. 2023 Feb;61(2):106711. doi: 10.1016/j.ijantimicag.2023.106711. Epub 2023 Jan 13.

Authors

Anette Veringa¹, Roger J Brüggemann², Lambert F R Span³, Bart J Biemond⁴, Mark G J de Boer⁵, Edwin R van den Heuvel⁶, Saskia K Klein⁷, Doris Kraemer⁸, Monique C Minnema⁹, Niek H J Prakken¹⁰, Bart J A Rijnders¹¹, Jesse J Swen¹², Paul E Verweij¹³, Mariëlle J Wondergem¹⁴, Paula F Ypma¹⁵, Nicole Blijlevens¹⁶, Jos G W Kosterink¹⁷, Tjip S van der Werf¹⁸, Jan-Willem C Alffenaar¹⁹; Voriconazole ZonMw Study Group

Affiliations

¹ Department of Clinical Pharmacy, OLVG, Amsterdam, the Netherlands; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. Electronic address: a.veringa@olvg.nl.
² Department of Pharmacy, Centre of Expertise in Mycology Radboudumc/CWZ and Radboud Institute of Health Science, University of Nijmegen, Radboudumc Nijmegen, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands.
³ Department of Haematology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
⁴ Department of Haematology, Amsterdam University Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
⁵ Department of Infectious Diseases, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.
⁶ Department of Mathematics and Computer Science, Eindhoven University of Technology, 5612 AZ, Eindhoven, the Netherlands.
⁷ Department of Haematology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands; Department of Haematology, Meander Medical Centre Amersfoort, Maatweg 3, 3813 TZ, Amersfoort, the Netherlands.
⁸ Department of Oncology and Haematology, Oldenburg Clinic, Rahel-Straus-Straße 10, 26133, Oldenburg, Germany.
⁹ Department of Haematology, University Medical Centre Utrecht, University Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherland.
¹⁰ Department of Radiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
¹¹ Department of Internal Medicine and Infectious Diseases, Erasmus University Medical Centre, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
¹² Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.
¹³ Department of Medical Microbiology, Radboudumc Nijmegen, the Netherlands; Centre of Expertise in Mycology Radboudumc/CWZ, Radboud University, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands.
¹⁴ Department of Haematology, VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
¹⁵ Department of Haematology, Haga Hospital, Els Borst-Eilersplein 275, 2545 AA, The Hague, the Netherlands.
¹⁶ Department of Haematology, Radboudumc Nijmegen, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands; Radboud Institute of Health Sciences, Geert Grooteplein Zuid 21, 6525 EZ, Nijmegen, the Netherlands.
¹⁷ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands; Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology & Economics, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
¹⁸ Department of Internal Medicine and Department of Pulmonary Diseases and Tuberculosis Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
¹⁹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands; Faculty of Medicine and Health, Sydney Pharmacy School, University of Sydney, Camperdown NSW 2006, Sydney, Australia; Westmead Hospital, Westmead, Sydney, NSW 2145, Australia.

PMID: 36642232
DOI: 10.1016/j.ijantimicag.2023.106711

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.

Publication types

Randomized Controlled Trial
Multicenter Study

MeSH terms

Adolescent
Adult
Antifungal Agents / adverse effects
Aspergillosis* / drug therapy
Drug Monitoring
Humans
Invasive Fungal Infections* / drug therapy
Prospective Studies
Retrospective Studies
Voriconazole / adverse effects

Substances

Voriconazole
Antifungal Agents

Associated data

ClinicalTrials.gov/NCT00893555