Guidelines for voriconazole blood concentration monitoring


Voriconazole is a relatively new azole antifungal drug that is increasingly used for fungal infections such as Aspergillus, Cryptococcus neoformans, Candida krusei, and fluconazole-resistant smooth Candida, and is especially recommended as the drug of choice for invasive Aspergillosis. Due to the drug in vivo pharmacokinetic individual differences and easy to interact with other drugs, intra- and inter-patient blood concentration differences, higher concentrations of toxicity and side effects are obvious, lower concentrations of efficacy is reduced, so the need to Guidelines for voriconazole blood concentration monitoringmonitor blood concentrations. The purpose is to develop and adjust individualized drug delivery programs to improve efficacy and ensure drug safety through blood concentration monitoring. Studies have shown that blood concentration monitoring of voriconazole in invasive fungal infections can effectively optimize the antimicrobial effect and reduce toxic side effects.


Voriconazole blood concentration correlates with efficacy and adverse effects but has a narrow therapeutic window

Adverse reactions of voriconazole are dominated by damage to the digestive system, nervous system, eyes and their accessory organs, with a high incidence of hepatotoxicity and neurotoxicity (encephalopathy, myasthenia gravis, hallucinations). Its adverse reactions, especially hepatotoxicity and neurotoxicity, limit the clinical application of voriconazole to some extent.

Individual variation in voriconazole blood concentrations is large

Adult oral voriconazole absolute bioavailability of up to 96%, about 0.5 ~ 2 h blood concentration peak, plasma protein binding rate of about 58%, the volume of distribution of the steady-state blood concentration of 4.6 L / kg, mainly through the liver metabolism, the body was non-linear pharmacokinetic characteristics, oral 200mg after the terminal half-life of about 6 h. However, due to drug interactions, age, bioavailability and other factors, the blood concentration of voriconazole varies greatly in different individuals.

Guidelines for voriconazole blood concentration monitoring


Voriconazole became available in the United States in 2002 and was listed as the drug of choice for invasive aspergillosis by the Infectious Diseases Society of America's Aspergillosis Guidelines in 2008, which also refer to limited information suggesting that blood concentration monitoring plays an important role in optimizing voriconazole's safety (and potentially efficacy as well). As research has progressed, in the last 5 years most guidelines have begun to recommend monitoring blood levels in patients using voriconazole for safe and effective clinical use. Some societies and organizations have also introduced standards for voriconazole blood concentration monitoring, detailing indications for blood concentration monitoring, target concentration ranges, and regimen adjustments. The guideline recommendations for voriconazole blood concentration monitoring indications are shown in table 2.

Guidelines for voriconazole blood concentration monitoring

As can be seen, blood levels should be monitored in most patients receiving voriconazole therapy in the presence of absorption or metabolism problems, occurrence of suspected adverse reactions, and severe invasive fungal infections. Blood levels should be monitored in most patients receiving voriconazole therapy, such as those with impaired or altered gastrointestinal function, hepatic insufficiency, intravenous sequential oral administration, concomitant or discontinuation of interacting medications, severe invasive fungal infections, poor therapeutic efficacy, occurrence of suspected adverse reactions, pediatrics, and transplant patients.


The guideline pointed out that voriconazole AUC/MIC, trough concentration/MIC ratio are related to the efficacy of voriconazole, the maximum efficacy can be reached when the trough concentration/MIC ratio of 2~5, the trough concentration can predict the efficacy and safety: monitoring the trough concentration is more convenient and feasible than the AUC; do not recommend routine monitoring of the peak concentration to predict the clinical efficacy. Therefore, when monitoring voriconazole blood concentration, it is recommended to monitor the steady state trough concentration.

Specimens for blood concentration monitoring should be collected within 30 min after the drug has reached steady state and before the next dose. When voriconazole is given as a loading dose, steady-state concentrations can be reached on day 3, while unloaded doses require 4-7 days to reach steady-state concentrations; therefore, it is recommended that the first monitoring time should not be earlier than the fifth dose (day 3) when a loading dose is given. The target concentrations, sampling times, and assay techniques recommended by the guidelines are shown in Table 3.

Guidelines for voriconazole blood concentration monitoring


If a conventional dose of voriconazole is given, only 49% (29/59) of the patients reach the blood level, which is a low rate of achievement. Therefore, it is important to both give a loading dose to bring blood concentrations to a rapid steady state and to individualize the design of a rational initial dosing regimen that takes into account the patient's age and incorporates factors such as drug-drug interactions. Children receiving voriconazole at 3 mg/kg or 4 mg/kg every 12 h show a linear clearance relationship, so to achieve blood levels in children similar to those in adults, the dose of voriconazole needs to be increased to ensure optimal blood levels and efficacy in pediatric patients. The initial dosing regimens for adults and children are shown in Table 4.

Guidelines for voriconazole blood concentration monitoring

Monitor steady-state trough concentrations after administration of the above regimen and subsequently adjust the dosing regimen based on the results. If the blood concentration monitoring results are not within the target range, the patient's medication compliance needs to be checked, the voriconazole dose needs to be adjusted, and concomitant medications with interactions need to be discontinued if necessary. The voriconazole dose was increased by 50% if the steady-state blood concentration test value was below the lower limit of the target concentration range (increased to 6 mg/kg administered every 12 h for intravenous administration in adults, and increased from 200 mg administered every 12 h to 300 mg administered every 12 h for oral administration), and the dose was reduced by 25% if the test value was above the upper limit of the target concentration range, and by 25% if the test value was above 10 μg/ mL or adverse events (e.g., hepatotoxicity, psychiatric/neurotoxicity:visual disturbances), one dose was discontinued, followed by a 50% reduction in the maintenance dose. Re-monitoring of voriconazole trough concentration levels after 2 to 5 days is recommended when adjusting voriconazole dose, sequential oral administration from a vein, or when adding or discontinuing drugs that affect voriconazole.


In summary, voriconazole has a very important role in antifungal therapy, with precise efficacy and wide application, with a reference range of therapeutic drug concentrations and toxicity levels, therapeutic effects, adverse effects and blood concentrations related to the pharmacokinetic profile can be affected by multiple factors such as patient age, route of administration, CYP450, drug-drug interactions, ethnicity, and polymorphisms in the CYP2C19 gene, and so on. Steady-state blood concentrations fluctuate widely. Therefore, it is recommended to monitor blood levels in most patients treated with voriconazole, such as patients with absorption or metabolism problems (especially drug-drug interactions), suspected adverse reactions, and severe invasive fungal infections. After reaching the steady-state blood concentration, blood should be drawn within 30 min before the next dose to monitor the trough concentration (the timing of the first monitoring should be no earlier than before the 5th dose); the reference value of the steady-state blood trough concentration is 1~5 μg/mL; and the dosage of the drug should be adjusted according to the results of the monitoring, so as to make voriconazole exert its therapeutic effects with high efficiency and low toxicity within the range of the target concentration. At present, voriconazole blood concentration monitoring is still in its infancy in China, and it is worthwhile to promote it in most medical institutions with a view to the safe and effective application of the drug.


Guidelines for voriconazole blood concentration monitoring

Guidelines for voriconazole blood concentration monitoring

Guidelines for voriconazole blood concentration monitoring


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