1. SlateRunPharma, inventor VORICONAZOLE- voriconazole injection, powder, lyophilized, for solution [Packet insert]2019 August 12, 2019.
5. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl). 1998;76(8):581–8. Epub 1998/08/07.
4. Moriyama B, Obeng AO, Barbarino J, Penzak SR, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2016. doi:
10.1002/cpt.583. PubMed PMID: 27981572; PubMed Central PMCID: PMCPMC5474211.
This section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2019 Statement from the US Food and Drug Administration (FDA)
CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism. Approximately 15 to 20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3 to 5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous normal metabolizer counterparts. Subjects who are heterozygous normal metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous normal metabolizer counterparts.
Please review the complete therapeutic recommendations that are located here:
(1)
2019 Statement from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2C19 Poor Metabolizers
The gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects. Initially, the risk of side effects is of particular interest.
Recommendation: Use 50% of the standard dose and monitor the plasma concentration
CYP2C19 Intermediate Metabolizers
The gene variation can reduce the conversion of voriconazole and consequently increase the plasma concentration. This could result in improved efficacy or an increase in the risk of side effects.
Recommendation: Monitor the plasma concentration
CYP2C19 Ultrarapid metabolizers
The gene variation increases the conversion of voriconazole, which increases the risk of ineffectiveness.
Recommendation: Use an initial dose that is 1.5x higher and monitor the plasma concentration
Background information
Mechanism:
Voriconazole is predominantly metabolised by CYP2C19 and otherwise by CYP2C9 and CYP3A4. The most important metabolite, voriconazole-N-oxide, is inactive.
For more information about CYP2C19 phenotypes: see the general background information about CYP2C19 on the KNMP Knowledge Bank or on www.knmp.nl (search for key word “CYP2C19”).
Other considerations:
Several studies indicate a higher risk of hepatotoxicity at higher plasma concentrations of voriconazole. However, the relationship between the plasma concentration and the effect or side effects (hepatotoxicity) has not been clearly identified.
The kinetics of voriconazole are non-linear at therapeutic doses.
Please review the complete therapeutic recommendations that are located here: (
5
).
2016 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
Clinical studies have not consistently demonstrated an association between CYP2C19 genotype and adverse reactions. However, as individual patients who are poor metabolizers may have elevated levels leading to toxicity, the use of another antifungal agent is recommended. Under circumstances in which voriconazole is strongly indicated for treatment of an invasive mycosis in a patient with a poor metabolizer phenotype, administration of a lower dosage with meticulous therapeutic drug monitoring may be feasible (Table 3).
Knowledge of CYP2C19 ultrarapid and rapid metabolizer genotypes may prevent subtherapeutic concentrations of voriconazole that may lead to treatment failure. In such cases, an alternative antifungal agent also is recommended, especially as several case reports have documented voriconazole treatment failure in CYP2C19 ultrarapid metabolizers (see Supplementary Table S1 online). Attempting to obtain therapeutic levels in patients with ultrarapid metabolizer genotypes are often unsuccessful. Serious delays in achieving therapeutic concentrations in such patients with active invasive mycoses may result in disease progression.
Several alternative agents may be used instead of voriconazole for treatment of invasive mold infections. These include isavuconazole, lipid formulations of amphotericin B, and posaconazole (Table 3). The antifungal triazole isavuconazole is approved for the primary treatment of invasive aspergillosis and invasive mucormycosis and is available in intravenous and oral dosage forms. As isavuconazole is a substrate of CYP3A4, variant alleles in this gene are unlikely to affect its clearance. Only limited data for isavuconazole are currently available in the pediatric population. Liposomal amphotericin B is an alternative therapy to voriconazole for the primary treatment of invasive aspergillosis. Posaconazole is currently indicated for salvage therapy of invasive aspergillosis. The recently approved posaconazole delayed release and intravenous dosage forms achieve higher concentrations than that of the posaconazole suspension. However, intravenous posaconazole requires administration via a central line due to phlebitis with peripheral administration. Similar to voriconazole, intravenous posaconazole also contains the solubilizer sulfobutylether-beta-cyclodextrin sodium. Posaconazole is cleared largely as unchanged compound with <20% of compound being excreted as a glucuronide conjugate. Uridine 50-diphospho- glucuronosyltransferase glucuronidation of posaconazole is not significantly affected by genetic variation. Administration of posaconazole should still be guided by TDM.
Please review the complete therapeutic recommendations that are located here:
(4).
Table 3. CPIC (2016) Dosing Recommendations for Voriconazole Treatment based on CYP2C19 Phenotype for Adults| a
. Rating scheme is described in Supplementary Data online (4). |
| b
. Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, therapeutic drug monitoring, and comorbidities. |
| c
. Recommendations based upon data extrapolated from individuals with CYP2C19*1/*17 genotype. |
| Please see Therapeutic Recommendations based on Genotype for more information from CPIC. This table is adapted from (4). |
| CYP2C19 phenotype | Implications for voriconazole pharmacologic measures | Therapeutic recommendations | Classification of recommendationsa
|
|---|
| CYP2C19 ultrarapid metabolizer (*17/*17) | In individuals for whom an ultrarapid metabolizer genotype (*17/*17) is identified, the probability of attainment of therapeutic voriconazole concentrations is small with standard dosing | Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.b
| Moderatec
|
| CYP2C19 rapid metabolizer (*1/*17) | In individuals for whom a rapid metabolizer genotype (*1/*17) is identified, the probability of attainment of therapeutic concentrations is modest with standard dosing | Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.b
| Moderate |
| CYP2C19 normal metabolizer | Normal voriconazole metabolism | Initiate therapy with recommended standard of care dosing.b
| Strong |
| CYP2C19 intermediate metabolizer | Higher dose-adjusted trough concentrations of voriconazole compared with normal metabolizers | Initiate therapy with recommended standard of care dosing.b
| Moderate |
| CYP2C19 poor metabolizer | Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events | Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.b
In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for an individual with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dos- age with careful therapeutic drug monitoring. | Moderate |
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The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.