Safety of Isavuconazonium Sulfate in Pediatrics Patients With Hematologic Malignancies and Hematopoietic Cell Transplantation With Invasive Fungal Infections: A Real World Experience

Abstract

Purpose: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population. Patients and Methods: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages. Results: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA. Conclusions: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Isavuconazole Treatment for Invasive Fungal Infections in Pediatric Patients

“…Our results align with previous reports, where patients received ISA as a salvage therapy for a proven IFI and showed a complete regression of the infection, with few adverse events and similar ISA exposure levels within the recommended range of 2–4 mg/L, as shown in Table 2 [ 6 , 7 , 8 , 10 , 11 ].…”

“…Considering the prolonged ISA half-life, we recommend closely monitoring ISA plasma levels, with a first ISA C trough 10 days after initiation, and then every 15 days during the maintenance period, in order to efficiently adapt ISA doses in this fragile population. Our findings aligned with prior reports [ 5 , 6 , 11 , 12 ] and highlight the need for guided-TDM therapy. Our results also showed the ability of our hospital pharmacists to personalize doses of ISA capsules, adapting them to patients <30 kg with guided-TDM therapy.…”

“…Articles and case reports suggest the administration of adult dosing in children over 30 kg, and half the dosing for children under 30 kg [ 6 , 7 , 8 , 9 ]. In those reports, tolerance, safety, and therapeutic response were evaluated, mostly in adolescent patients [ 6 , 10 , 11 ]. This work’s objective was to assess the safety of ISA in the pediatric population.…”

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

“…All other limited available evidence of isavuconazole in the pediatric setting refers to the treatment of invasive aspergillosis or mucormycosis as salvage therapy after clinical failure with first-line therapies. 18,19,[34][35][36][37][38][39][40][41][42] Overall, this comparative study confirms that even in a pediatric setting, an approach based on real-time CPAs performed by MD clinical pharmacologists and based on TDM results should be considered mandatory when using voriconazole, whereas the same approach should not be necessary in most cases involving isavuconazole. Notably, the implementation of a similar real-time CPA program should be carefully considered in centers managing pediatric patients with hemato-oncological malignancies requiring high-intensity treatment to personalize and maximize antifungal prophylaxis or treatment.…”

“…[15][16][17] However, in the pediatric setting, the use of isavuconazole has been investigated in a small number of real-world cases involving pediatric hemato-oncological patients. 18,19 The need for dosing personalization using CPAs based on TDM may be less necessary for isavuconazole than for voriconazole, considering that, according to the pharmacokinetic features, the expected intra-and interindividual variability during fixed dosing regimens should be lower. 20,21 Besides, for isavuconazole, recent studies have proposed a therapeutic range of C min between 1.0 and 5.1 mg/L for maximizing efficacy and minimizing toxicity risk.…”