Variability of Isavuconazole Trough Concentrations during Longitudinal Therapeutic Drug Monitoring

Abstract

Isavuconazole (ISA), a triazole antifungal agent, is licensed for the treatment of invasive aspergillosis and mucormycosis. Therapeutic drug monitoring (TDM) is a cornerstone of treatment efficacy for triazole antifungals due to their pharmacokinetic variability, except for ISA, for which the utility of TDM is still uncertain. We performed a retrospective study that aimed to assess the inter- and intra-individual variability of ISA trough concentrations (Cmin) and to identify the determinants involved in such variability. ISA Cmin measured in adult patients at the Grenoble Alpes University Hospital between January 2018 and August 2020 were retrospectively analyzed. In total, 304 ISA Cmin for 33 patients were analyzed. The median ISA Cmin was 2.8 [25th–75th percentiles: 2.0–3.7] mg/L. The inter- and intra-individual variability was 41.5% and 30.7%, respectively. Multivariate analysis showed independent covariate effects of dose (β = 0.004 ± 3.56 × 10−4, p < 0.001), Aspartate aminotransférase (ASAT) (β = 0.002 ± 5.41 × 10−4, p = 0.002), and protein levels (β = 0.022 ± 0.004, p < 0.001) on ISA Cmin, whereas C reactive protein levels did not show any association. This study, conducted on a large number of ISA Cmin, shows that ISA exposure exhibits variability, explained in part by the ISA dose, and ASAT and protein levels.

Clinical Features and Treatment Progress of Invasive Mucormycosis in Patients with Hematological Malignancies

“…However, real-life studies demonstrated inter-patient variability in isavuconazole exposure (coefficients of variation of 51% for area under the plasma concentration-time curve and 59% for trough plasma concentration) [82] and relationships between isavuconazole blood concentrations and side effects [83]. Bolcato et al and Höhl et al also found that factors such as body mass index ≥ 25, higher sepsis-related organ failure assessment score, aspartate aminotransferase, and protein levels were associated with isavuconazole exposure variability [84]. Further studies are needed to investigate the variability of isavuconazole trough concentrations and its role on drug efficacy and/or toxicity.…”

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

“…The duration of treatment with an antifungal is around six to twelve weeks, but it can take months for up to over a year [ 80 ]. For the treatment of invasive aspergillosis (IA), the most recently used therapy has been isavuconazole, showing a high efficacy in the treatment of aspergillosis in immunocompromised patients, a lower potential for Drug–Drug Interactions (DDIs), and no risk of QT prolongation (heart rhythm disturbance) that can cause a rapid and chaotic heartbeat [ 82 , 83 , 84 ].…”