Role of a TDM-guided strategy of isavuconazole for optimizing efficacy/safety outcomes in onco-hematological pediatric patients: a systematic review

Introduction: Evidence concerning the implementation of a therapeutic drug monitoring (TDM)-guided approach for optimizing isavuconazole exposure in oncohematological pediatric patients are limited. The aim of this systematic review is to summarize the current evidence about the role that a TDM-guided strategy of isavuconazole may have in optimizing efficacy/safety outcomes of invasive fungal infections (IFI) treatment/prophylaxis among onco-hematological pediatric patients. Methods: Two authors independently searched the PubMed-MEDLINE and Scopus databases up to 25 April 2025, to retrieve randomized controlled trials or observational studies providing real-life data assessing isavuconazole exposure according to a TDM-guided approach in pediatric patients, and evaluating the relationship between isavuconazole exposure and efficacy/safety outcomes. Data were independently extracted by the two authors, and the quality of the included studies was independently assessed by means of specific tools according to study design. Mortality attributable to IFI and hepatotoxicity occurrence were selected as primary outcomes. Descriptive statistics were used for summarizing the retrieved data. Results: After screening 577 articles, eight studies were included in the systematic review (five retrospective observational cohort studies and three case series; n=116). Attainment of optimal isavuconazole exposure at first TDM assessment ranged from 36.7% to 83.3% of included patients, being underexposure reported in up to 40.0% of cases. Overall, mortality attributable to IFI occurred in 10 out of 59 patients (16.9%) in which this outcome was evaluated, being associated with isavuconazole overexposure only in 30.0% of cases. Hepatotoxicity occurred in 14 out of 78 included patients (17.9%), being related to isavuconazole overexposure in 50.0% of cases. Conclusion: Despite limited findings, our systematic review may support a potential role for a TDM-guided strategy in optimizing isavuconazole exposure among oncohematological pediatric patients, particularly considering both the non-negligible proportion of cases who failed in attaining optimal exposure with standard dosing regimens.