Six days after increasing the dose, the voriconazole concentration was still below where it should have been and a decision was made to switch to IV voriconazole on day 40; on day 44 the dose was increased to 300mg IV every 12 hours. After reviewing the patient’s medication records, clinicians believed that dexamethasone, which had been initiated at the start of voriconazole treatment, was most likely the cause of subtherapeutic voriconazole concentrations due to its interaction with CYP enzymes. On day 37 of treatment, a decision was made to taper dexamethasone dose and with that a rise in voriconazole concentrations was seen as dexamethasone was removed. On day 52, the patient was switched back to oral voriconazole 300mg every 12 hours and was discharged on day 53. An improvement in cognitive function was noted on day 57 of treatment.
Voriconazole is an azole antigungal and is metabolized by CYP2C19, CYP2C9, and CYP3A4; inducers of these three enzymes may decrease voriconazole systemic exposure. Dexamethasone is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. The induction of these enzymes can lead to rapid metabolism of voriconazole and subtherapeutic concentrations as seen in this patient. Only two other articles have been identified which describe this interaction however this case is the first to report the “prospective time course and clinical impact of this interaction.” Previous studies with prednisone and prednisolone have demonstrated no impact on voriconazole concentrations. In this case, despite increasing the dose to 4mg/kg, target troughs (voriconazole concentration of 2mcg/L) were not achieved. After changing to the IV formulation, clinicians ruled out the possibility of inadequate oral absorption and started to consider interacting medications. Based on the timing and the CYP induction potential, dexamethasone was identified as the offender. Using the Drug Interaction Probability Scale this interaction scored a 7 out of 10 indicating probable interaction.
Because results for voriconazole concentrations can take up to a week, for patients on concomitant dexamethasone, the authors recommend maintaining a dose of 4mg/kg every 12 hours, however tapering and discontinuation of dexamethasone could result in increased voriconazole concentrations and possibly increased adverse events (ie, CNS and liver toxicity). The authors state that “if possible, consideration should be given to other steroid options that have not demonstrated as significant an impact on voriconazole concentrations, for example prednisone or prednisolone.”
K. L. Wallace, R. L. Filipek, R. M. La Hoz, J. C. Williamson. Subtherapeutic voriconazole concentrations associated with concomitant dexamethasone: case report and review of the literature. Journal of Clinical Pharmacy and Therapeutics. 2016. doi: 10.1111/jcpt.12401