Evaluation of voriconazole TDM in malignant hematology patients
发布日期:
2025-01-17
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In patients with malignant hematological diseases (MH), who are prone to invasive fungal infections (IFIs) due to their chronically neutropenic state and treatment with immunosuppressive drugs, voriconazole is often used for treatment or prophylaxis for this reason. Given the large inter- or intra-individual variability in voriconazole blood concentrations, the many interfering factors, and the prone to adverse effects, patients treated with voriconazole commonly require monitoring of drug concentrations (TDM) to ensure that trough concentrations of the drug are maintained within therapeutic range (usually at the level of 1-5 mg/L).

Although TDM for voriconazole has been gradually promoted, there is not much literature that specifically describes the level of control of voriconazole in hospitals. The Princess Margaret Cancer Center (PM), where this study was conducted, considers voriconazole TDM to be routinely tested, and the investigators collected some data to retrospectively analyze the pattern of voriconazole concentrations in patients, as well as to observe the safety of voriconazole with supratherapeutic trough concentrations.



Results





In order to identify the reasons for the fluctuation in voriconazole concentration in the later data analysis, the enrolled subjects were all inpatients of this hospital and their first dose had to be administered in the hospital. In addition to the trough concentrations of the drugs, several data were collected, including the reason for administration, hepatic and renal function status, and concomitant use of other interacting drugs.

Based on the above criteria, a total of 56 patients were enrolled in this study. Of the initiate voriconazole trough concentration test, 41 (73.2%) reached the therapeutic range (1-5 mg/L). Of these, 30 (73.2%) maintained concentrations within the therapeutic range throughout treatment; 10 (24.4%) were out of range in level 2 (7 were ultrahigh and 3 were below the effective range), and 1 (2.4%) was out of range (low) in level 3. Of the 15 patients who were out of range in the initial assay, 11 (73.3%) were supratherapeutic, and 4 ( 26.7%) had subtherapeutic. In addition, 8 of these 15 patients had dose-adjusted blood concentrations restored to the therapeutic range, while 7 discontinued voriconazole treatment because of adverse effects or other reasons (as shown in Figure I).


Evaluation of voriconazole TDM in malignant hematology patients


FigureFlow diagram for voriconazole therapeutic drug monitoring


In the duration of treatment, 23 (41.1%) experienced adverse effects, and of these, 8 (34.8%) were found to be supratherapeutic. Table 1 describes in detail the diagnosis, infection and subsequent treatment of these 8 patients. 19 patients experienced transaminitis, 3 patients experienced both transaminitis and neurotoxicity, 1 patient experienced photopsia. For transaminitis specifically, there were 28 distinct episodes in total with 12 (42.9%) instances of Grade 1 transaminitis; 12 (42.9%) of Grade 2; 3 (10.7%) of Grade 3; and 1 (3.5%) of Grade 4. Of the 23 patients who experienced adverse effects, 5 (21.7%) discontinued voriconazole therapy.


39 patients were receiving at least one of the interacting drugs that may interference voriconazole metabolism. These drugs included the proton pump inhibitors pantoprazole and fluoxetine (which can theoretically increase voriconazole levels), and the CYP2C19 inducer letermovir (which can decrease voriconazole level). Thirty-four of them received pantoprazole during treatment. 25 of these 34 had an initial level within therapeutic range, 6 had a supratherapeutic initial level, 3 had a subtherapeutic initial level, and 18 patients experienced adverse effects (4 of them were supratherapeutic). 1 patient took letermovir but had initial level within therapeutic range and did not experience adverse effects. 2 patients received both pantoprazole and letermovir with level within therapeutic range and no adverse effects. However, 1 patient received both pantoprazole and fluoxetine and was supratherapeutic, but did not experience adverse effects.

Table 1. Patients who experienced adverse effects with supratherapeutic levels (n = 8).

Evaluation of voriconazole TDM in malignant hematology patients



Conclusion






One of the objectives of the study was to observe whether voriconazole blood levels were within the therapeutic range for patients on standardized therapeutic dosing and the associated incidence of adverse effects.

73% of the initiate drug level obtained in this study were within the therapeutic range, which is higher than the previously reported value of 53% [1], whereas the percentage of supratherapeutic levels (21.4%) was lower than previously reported (26%)[2]. Factors contributing to this discrepancy may be that different studies defined different ranges of normal reference values or that the timing of blood collection was set differently. In addition, the study performed medication adjustments for 26 cases of outside the therapeutic range, of which 17 returned to normal, which shows that voriconazole TDM is helpful in clinical dosing.

The 41.1% incidence of adverse effects in this study was similar to that reported in other studies (42%) [3]However, only 34.8% (8 patients) of the patients who experienced adverse effects had blood levels that were supratherapeutic. It is difficult to directly link the occurrence of these adverse effects to high voriconazole blood levels, and it can be hypothesized that voriconazole at normal levels may also cause adverse effects. However, all three patients with neurotoxic adverse effects in the current study had supratherapeutic voriconazole trough concentrations (>5.5 mg/L), whereas the others did not.

The limitation of this literature is that the sample size is still very small, and therefore it is still not possible to give a definitive conclusion when some of the characteristic changes are found. For example, this study found that all three patients with neurotoxicity had high drug concentrations, but it cannot be attributed to the fact that neurotoxicity occurs only with high drug concentrations.






Evaluation of voriconazole TDM in malignant hematology patients

Evaluation of voriconazole TDM in malignant hematology patients

Evaluation of voriconazole TDM in malignant hematology patients



Reference:

1. Sebaaly, J.C., S.H. MacVane, and T.B. Hassig, Voriconazole concentration monitoring at an academic medical center. Am J Health Syst Pharm, 2016. 73(5 Suppl 1): p. S14-21.

2. Yi, W.M., et al., Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study. Ann Clin Microbiol Antimicrob, 2017. 16(1): p. 60.

3. Park, W.B., et al., The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis, 2012. 55(8): p. 1080-7.





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