Impact of genetic variation on response to therapy
Voriconazole is extensively metabolised by CYP2C19. The SmPC states that pharmacokinetic studies have demonstrated that CYP2C19 poor metabolisers have on average 4-fold higher voriconazole exposure (AUC) versus normal metabolisers, and intermediate metabolisers have on average 2-fold higher voriconazole exposure versus normal metabolisers.
Voriconazole demonstrates wide interpatient variability in plasma concentrations, due in part to genetic polymorphism in the CYP2C19 gene. The SmPC for voriconazole recommends individual dose adjustment according to response. Knowledge of a patient’s CYP2C19 metaboliser phenotype may help guide this by identifying patients who are at an increased risk of experiencing adverse effects or treatment failure.
Testing recommendations
At the time of publication, there are no recommendations for CYP2C19 genotype testing to determine voriconazole dose in the UK.
Therapeutic recommendations
CYP2C19 metaboliser status unknown
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Ultra-rapid metabolisers
Some examples of CYP2C19 genotypes include: *17/*17
- Predictive of lower plasma exposure than normal and rapid metabolisers.
- Probability of attaining therapeutic voriconazole concentrations is low.
- Increased likelihood of treatment failure.
- Consider an alternative agent not dependent on CYP2C19 metabolism.
CYP2C19 Rapid metabolisers
Some examples of CYP2C19 genotypes include: *1/*17
- Predictive of lower plasma exposure than normal metabolisers.
- Probability of attaining therapeutic voriconazole concentrations with standard dosing may be variable.
- Increased risk of therapeutic failure.
- Initiate at standard starting dose, use therapeutic drug monitoring and titrate according to response with a low threshold for increasing the dose.
CYP2C19 Normal metabolisers
Some examples of CYP2C19 genotypes include: *1/*1
- Initiate treatment with standard starting dose.
- Monitor for efficacy and adverse effects and titrate according to response.
CYP2C19 Intermediate metabolisers
Some examples of CYP2C19 genotypes include: *1/*2, *1/*3, *2/*17, *3/*17
- Predictive of higher plasma concentrations than normal metabolisers.
- Initiate treatment with standard starting dose.
- Use therapeutic drug monitoring and titrate according to response with a low threshold for decreasing the dose.
CYP2C19 Poor metabolisers
Some examples of CYP2C19 genotypes include: *2/*2, *3/*3, *2/*3
- Predictive of higher plasma concentrations than normal and intermediate metabolisers.
- Increased probability of adverse effects.
- Consider an alternative agent not dependent on CYP2C19 metabolism.
- If a suitable alternative is not available and treatment with voriconazole is still warranted, initiate with a standard loading dose, followed by a 50% reduction of the standard maintenance dose.
- Use therapeutic drug monitoring and titrate according to response with a low threshold for decreasing the dose.
Further information
Voriconazole is metabolised by, and inhibits the activity of CYP isoenzymes CYP2C19, CYP2C9, and CYP3A4. There is a potential for drug interactions with inhibitors, inducers and substrates of CYP2C19, CYP2C9 and CYP3A4. Consult the SmPC for more detailed information on drug interactions.
Many factors including non-genetic factors can contribute to the variability in response to voriconazole including co-morbidities, inflammation, drug interactions, renal function, and hepatic function. These may be additive to the effect of genotype on drug metabolism and response. Genetic and non-genetic factors must be considered in the clinical context of an individual patient when applying the suggested dose modifications.
Alternative antifungal agents not dependent on CYP2C19 metabolism include liposomal amphotericin-B and posaconazole, seek advice from infection experts.
References
Pfizer Limited (2024). VFEND 200mg film-coated tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/8408/smpc (Accessed online 3 July 2025).
Clinical Pharmacogenetics Implementation Consortium (2016) Guideline for CYP2C19 Genotype and Voriconazole Therapy. Available at: https://cpicpgx.org/guidelines/guideline-for-voriconazole-and-cyp2c19/ (Accessed online 3 July 2025).
Dutch Pharmacogenetics Working Group Pharmacogenetic Recommendation Text (20230801 update). Available at: https://www.knmp.nl/dossiers/farmacogenetica Information in English available at: https://www.knmp.nl/dossiers/farmacogenetica/pharmacogenetics (Accessed online 8 July 2025).
