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

• Published in: International journal of antimicrobial agents 2023-02, Vol.61 (2), p.106711, Article 106711
• Main Authors: Veringa, Anette, Brüggemann, Roger J., Span, Lambert F.R., Biemond, Bart J., de Boer, Mark G.J., van den Heuvel, Edwin R., Klein, Saskia K., Kraemer, Doris, Minnema, Monique C., Prakken, Niek H.J., Rijnders, Bart J.A., Swen, Jesse J., Verweij, Paul E., Wondergem, Mariëlle J., Ypma, Paula F., Blijlevens, Nicole, Kosterink, Jos G.W., van der Werf, Tjip S., Alffenaar, Jan-Willem C.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antifungal Agents - adverse effects; Aspergillosis - drug therapy; Drug Monitoring; Haematological malignancy; Humans; Invasive fungal infection; Invasive Fungal Infections - drug therapy; Prospective Studies; Retrospective Studies; Therapeutic drug monitoring; Voriconazole; Voriconazole - adverse effects
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.106711

•80.9% of all haematological patients with invasive aspergillosis had an initial voriconazole concentration (measured around 3 days after treatment initiation) within 1-6 mg/L after standard dosing of voriconazole•Therapeutic Drug Monitoring resulted in 10% more voriconazole concentrations within the therapeutic range during voriconazole treatment•TDM guided dosing of voriconazole did not result in a clinical improvement of ≥ 20% (including both response to treatment and treatment discontinuation due to an adverse drug reaction)•A more targeted approach for TDM of voriconazole might be the way forward, but this should be confirmed in a follow-up study 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. 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. 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). 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. ClinicalTrials.gov registration no. NCT00893555.