Serial monitoring of isavuconazole blood levels during prolonged antifungal therapy

Abstract

Background Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. Objectives To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. Methods From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. Results A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64–8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023–0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity. Conclusions Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Isavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations

“…In our cohort ISA was used for treatment of invasive fungal diseases in patients with malignant and non-malignant underlying diseases. Overall, ISA was well tolerated compared to previous studies [ 4 , 10 ]. Eighteen percent had adverse events during treatment including one ISA case with suspected immediate allergic reaction.…”

“…However, no clinical data were available, and therefore the study could not assess potential associations between ISA levels and efficacy and safety events [ 9 ]. This limitation was overcome by a second recent study showing that prolonged administrations and high serum levels of ISA may be associated with adverse events [ 10 ]. However, that study was limited by a relatively small sample size (19 patients), all with underlying malignant diseases (18 hematological and one solid), necessitating validation of these findings in other trials and other patient cohorts.…”

Mucormycosis

“…256 It has been noted in a small study that levels of 2.86 mg/L after 14 days of therapy and 4.4 mg/L after 42 days of therapy were observed in seven cancer patients successfully treated for proven/probable aspergillosis or mucormycosis and that ISAV trough levels increased over time, with higher levels being associated with adverse effects. 257 Still, no threshold ISAV levels have definitively been correlated thus far with efficacy or toxicity. 257,258 Combination Antifungal Therapy Combination therapy with two or more antifungal agents has been used in refractory cases of mucormycosis, 169,259 but RCTs are lacking.…”

“…257 Still, no threshold ISAV levels have definitively been correlated thus far with efficacy or toxicity. 257,258 Combination Antifungal Therapy Combination therapy with two or more antifungal agents has been used in refractory cases of mucormycosis, 169,259 but RCTs are lacking. 260 Pagano et al reported 32 patients from two large European registries between 2007 and 2012 with proven/probable mucormycosis treated with a combination of POSA and LFAB.…”

Treatment of invasive fungal diseases in cancer patients—Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

“…Plasma concentrations between 2 and 4 mg/L are considered as adequate (CIII). A potential threshold for toxicity (mainly gastrointestinal) was observed in patients during therapy with isavuconazole with serum concentrations exceeding 4.8 mg/L 313 . However, therapeutic target levels are not well defined.…”