The pharmacokinetic challenge of voriconazole therapy for cerebral aspergillosis in patients treated with ibrutinib
- 230 Downloads
Acute respiratory distress syndrome
Chronic lymphocytic leukemia
Central nervous system
Intensive care unit
Magnetic resonance imaging
Ibrutinib is a new Bruton’s tyrosine kinase inhibitor approved for the management of chronic lymphocytic leukemia (CLL) that has recently been associated with an increasing number of cases of invasive aspergillosis (IA). Ghez et al. reported 33 patients with invasive fungal infections, corresponding to IA in 27/33 with cerebral aspergillosis in 40% of these cases . Voriconazole (VRCZ) is the first-line treatment for IA including central nervous system (CNS) infection due to its good penetration across the blood-brain barrier. However, VRCZ requires therapeutic drug monitoring to ensure effective therapy. In the case reported here, CNS aspergillosis was responsible for brain edema requiring corticosteroids. However, corticosteroids have been very recently reported to be a new cause of rapid VRCZ metabolism, inducing low plasma VRCZ concentrations and therefore limited efficacy .
The reduction of plasma VRCZ levels is a poorly known effect by physicians associated with concomitant corticosteroid therapy, as corticosteroids are potent inducers of CYP2C19 and CYP3A in humans, both of which are implicated in VRCZ metabolism . Also inflammation, as reflected by the C-reactive protein (CRP) concentration, also increases plasma VRCZ concentrations as a result of decreased metabolism . Corticosteroid therapy can therefore lead to a rapid decrease of plasma VRCZ concentrations.
This situation could become increasingly frequent in view of the growing number of cases of CNS aspergillosis observed in patients treated with ibrutinib. Physicians must therefore be aware of the drug-drug interaction between VRCZ and corticosteroids for cytochrome P450, which can lead to decreased plasma VRCZ concentrations and therefore limited efficacity against the Aspergillus.
Availability of data and materials
All data generated or analysed during this study are included in this published article.
RN wrote the manuscript and performed the literature search. RN, LS and CD performed data acquisition. TC performed galactomannan antigen assay and BAL culture, YB performed therapeutic drug monitoring. RN, EZ, TC and JM analyzed the data and approved the final manuscript. All authors accepted the final version of the manuscript.
Ethics approval and consent to participate
According to French legislation, the patient was informed and accepted in the department of hematology that data concerning his case might be subsequently used for scientific analyses and could be published with anonymized data.
Consent for publication
This paper concerns a retrospective case report of an individual patient. According to French legislation, the patient was informed and accepted in the department of hematology that data concerning his case might be subsequently used for scientific analyses, and could be published with anonymized data.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.