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).