The pharmacokinetic challenge of voriconazole therapy for cerebral aspergillosis in patients treated with ibrutinib

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 [1]. 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 [2].

A 69-year-old man with a history of refractory CLL treated with ibrutinib was admitted to the ICU with ARDS (acute respiratory distress syndrome) secondary to invasive pulmonary aspergillosis (Fig. 1a–c). Therefore, intravenous VRCZ was initiated and ibrutinib was stopped. Three weeks later, brain MRI was performed following the onset of neurological signs and revealed bilateral nodular lesions consistent with cerebral IA associated with brain edema requiring corticosteroids (methylprednisolone) (Fig. 1d). Corticosteroid therapy significantly reduced brain edema and improved clinical symptoms. However, several days after, a new elevation of galactomannan (GM) antigen was observed in serum and BAL fluid despite VRCZ therapy. Elevated galactomannan was associated with a marked decrease of plasma VRCZ concentrations, requiring an increase of the VRCZ dosage (Fig. 2). Corticosteroids were stopped 2 weeks later, followed by a marked increase of plasma VRCZ concentrations and negative GM antigen (Fig. 2).

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 [3]. Also inflammation, as reflected by the C-reactive protein (CRP) concentration, also increases plasma VRCZ concentrations as a result of decreased metabolism [2]. Corticosteroid therapy can therefore lead to a rapid decrease of plasma VRCZ concentrations.