Discussion
Voriconazole is a triazole antifungal agent that is a first-line drug
applied in the treatment of a wide number of fungal infections,
including pulmonary invasive aspergillosis, fluconazole-resistant
Candida spp.10-13 Voriconazole is metabolized by
cytochrome P450 (CYP), mostly by the CYP2C19 isoenzyme and, to a lesser
extent, by CYP3A4 and CYP2C9. CYP2C19*1 is the wild-type allele with
enzymatic activity, whereas the most common loss-of-function alleles are
CYP2C19*2 and CYP2C19*3.14. Individuals having one
functional allele plus one loss-of-function allele are also referred to
as intermediate metabolizers. There were higher dose-adjusted trough
concentrations of Voriconazole in intermediate metabolizers compared
with normal metabolizers; therefore, the Dutch Pharmacogenetics Working
Group recommended standard of care dosing and monitoring of the plasma
concentration. In theory, our patient was determined to be an
intermediate metabolizer with CYP2C19*1/*2 accompanied by a higher
concentration of voriconazole due to the absence of a functional CYP2C19
enzyme; however, the experience in this patient’s second exposure to
voriconazole did not coincide with the abovementioned interpretation and
could not completely explain such obvious and long-term loss with
adsorption of the ECMO circuit.
Because CYP2C19 activity was impaired, other metabolic pathways, such as
the CYP3A-mediated pathway, may have become the major clearance
mechanism and been influenced by CYP3A modulators. Brad and his
colleagues explored a poor metabolizer with CYP2C19*2/*3 coadministered
vincristine, a CYP3A4 inhibitor, which induced a significant increase in
voriconazole concentration15. Sara et al., Li et al.,
and Andreas et al. discovered a 2-way interaction between voriconazole
and other drugs connected to the CYP2C19 genotype and concomitant
medication8,9,16. Therefore, we hypothesized that
CYP2C19 activity may be impaired in patients who metabolize voriconazole
mainly via CYP3A or/and CYP2C9; therefore, concomitant strong
CYP3A4/CYP2C9 inhibitors might decrease voriconazole metabolism and
increase its concentration. In this case, ritonavir is a CYP3A4
inhibitor, which may decrease voriconazole metabolism. Furthermore,
azithromycin, a strong CYP3A4 inhibitor, was prescribed from the
27th to the 31st of January, and the
inhibitory effect of azithromycin should not be ignored because the
published mean CYP3A4 turnover half-life values ranged from 10 to 140 h.
Using the highest estimate, recovery of full CYP3A4 activity may
therefore take up to 23-29 days (4-5 turnover half-lives) after complete
inhibition18. Therefore, though azithromycin was
stopped 3 days before voriconazole use, its effect on CYP3A4 inhibition
should be taken into account.
For CYP2C19 IMs and PMs, taking voriconazole with concurrent potent
CYP3A inhibitors would result in a substantially higher risk of
developing severe adverse events (AEs), including neurotoxicity and
hepatotoxicity. In this case, the consciousness of the patient did not
improve even when the infection was controlled and the dose of sedatives
was reduced until voriconazole was withdrawn; therefore, neurotoxicity
of voriconazole could not be excluded (data not shown).