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Utility of triazole antifungal therapeutic drug monitoring

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Triazole antifungal agents (fluconazole, isavuconazole, itravuconazole, posaconazole and voriconazole) are used in practice for prevention and treatment of invasive fungal infections. Due to the variable pharmacokinetics and known drug-drug interactions (DDIs), the use of these drugs in practice is complicated. Therefore, therapeutic drug monitoring (TDM) is commonly recommended to monitor drug concentrations. The results of a recent large multi-center study in America shows that in approximately half of patients receiving posaconazole or voriconazole TDM was performed, despite these recommendations. McCreary et al. has summarized some utilities of the Society of Infectious Diseases Pharmacists to emphasize TDM use during treatment with triazole antifungal agents. The utilities described in the article are indication, PK considerations, sample (parent drug and/or metabolites), timing sample, type is assay, target concentrations, toxic concentrations, PD targets and recommendations for dose adjustments. Below the indication for TDM and dose adjustment recommendation per antifungal agent is explained, due this applies to DDI management with azoles. For itraconazole, voricanozole, and posaconazole, TDM should be routinely employed during prophylaxis or treatment and especially with a dose adjustment or new comedication with a drug-drug interaction. TDM is recommended for fluconazole and isavuconazole in specific circumstances.

The advice for itraconazole is to perform TDM when capsules (prophylaxis and treatment) and suspension or SUBA-itraconazole capsule (prophylaxis) are used and consider TDM for suspension or SUBA-itraconazole capsule when used for treatment. When a dose adjustment is required, an increment between 50 and 100 mg can be chosen.

TDM for posaconazole is recommended for immediate-release suspension (prophylaxis or treatment) and direct release tablet, suspension or intravenous (prophylaxis) and consider TDM for direct release tablet, suspension or intravenous (treatment). For direct release tablet increments of 100 mg can be performed.

TDM should be routinely employed for prophylaxis and treatment with voriconazole, due to intra- and inter-patient pharmacokinetic variability with dosing and the association of toxicity. Dose adjustment can be made with the help of dosing algorithms Bayesian software.

TDM for fluconazole is uncommon, but can be considered in special populations with concern for treatment failure, such as pediatric patients, patients with reduced absorption and patients receiving continuous renal replacement therapy. Dose increments of 200 mg can be performed for intravenous and oral fluconazole.

The specific circumstances for TDM for isavuconazole concentrations are for patients receiving alternative methods of administrations (e.g. via enteral feeding tubes, opened capsules), critical illness, extremes of weight, refractory infections, pediatric, drug-drug interactions or other factors that alter pharmacokinetics. For intravenous or oral isavuconazole, dose increments of 186 mg can be performed (186 mg isavuconazonium sulfate = 100 mg isavuconazole).

Link to full article: Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists - McCreary - 2023