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 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

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

. 2023 Feb;61(2):106711.

doi: 10.1016/j.ijantimicag.2023.106711. Epub 2023 Jan 13.

Authors

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.

PubMed Disclaimer

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.

Comment in

Comment on 'Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: A multicentre, prospective, cluster randomised, crossover clinical trial'.
Gautier-Veyret E, Thiebaut-Bertrand A, Stanke-Labesque F. Gautier-Veyret E, et al. Int J Antimicrob Agents. 2023 Aug;62(2):106853. doi: 10.1016/j.ijantimicag.2023.106853. Epub 2023 May 18. Int J Antimicrob Agents. 2023. PMID: 37209956 No abstract available.

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical