Real-World Comparison of Isavuconazole and Voriconazole in Terms of the Need for Dosage Adjustments Guided by Clinical Pharmacological Advice During Primary Prophylaxis of Invasive Fungal Infections in Pediatric Patients with Hemato-Oncological Malignancies

Abstract

Background:Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients.Methods:Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero–Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(Cmin)/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated.Results:Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole (P < 0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002).Conclusions:Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis resulting in a low need for CPA-guided dosage adjustments.

Novel Insights into Fungal Infections Prophylaxis and Treatment in Pediatric Patients with Cancer

“…Isavuconazole at the studied dose of 10 mg/kg was generally well tolerated and showed an overall safety profile similar to that observed in adults; moreover, plasma drug exposure was comparable to that observed in adults in phase 3 efficacy trials [ 107 ]. More recent data [ 108 ] suggested that the variability of isavuconazole exposure in hematological pediatric patients could be low: the analysis of 16 patients showed that dosage adjustment for isavuconazole was required in 3.3% of cases ( p < 0.001) and at the first real-time therapeutic drug monitoring, the reach of the desired target was higher for isavuconazole than voriconazole (83.3% vs. 10%, p = 0.008) [ 105 ].…”