Voriconazole (VCZ) therapeutic drug monitoring (TDM) for prophylaxis and treatment of invasive fungal diseases in hematology patients – daily clinical practice and evidence from clinical trials

Abstract Invasive fungal diseases (IFD) are a life-threatening complication during treatment of hematological malignancies. VCZ is approved for the treatment of invasive aspergillosis, candidemia in non-neutropenic, and other serious mold infections in adults and pediatric patients (pts) aged >2 years. VCZ has been studied as IFD prophylaxis in neutropenic pts (EMA approval). VCZ exhibits considerable variability of drug exposure with a potential risk of under or overdosing, furthermore, potential drug-drug interactions (DDI) due to strong inhibition of CYP3A4 are noteworthy. Potential factors influencing VCZ plasma levels have been identified. TDM of VCZ is recommended by guidelines to improve outcome results for management of IFD and avoid adverse effects, in particular hepatic toxicity, visual disturbances, photosensitivity, and neurological toxicity. A VCZ trough concentration between 1.0-5.5 mg/L is widely accepted as target range. We evaluated published studies between 1995 and 2025 with evidence-based criteria for TDM of VCZ in order to assess whether TDM improves efficacy and safety of VCZ for IFD management. Our study aims to analyze the evidence of VCZ TDM for daily clinical practice with particular focus for certain subgroups of hematology pts as children, renal failure and obese pts. Material and Methods: We identified a total 32 clinical trials including 4271 pts (range 5 – 1091). In a total of 4228 patients (381 (9%) children and 3847 (91%) adults), efficacy or safety could be evaluated. For each study a QoE-level and the strength of recommendation were given with the GRADE and AGREE systems. Strength of evidence was classified as strong (A), moderate (B) or marginal (C) and against (D) and quality of evidence Level I to III to support a recommendation respectively. Results: Out of a total of 32 studies, 9 studies were prospectively performed, but only 2 as prospective randomized and one as a prospective double-blind trial. Evidence for TDM regarding efficacy was evaluable from 15 out of 32 trials, 13 TDM trials were evaluable with respect to toxicity, and 9 provided data for both efficacy and toxicity. Only 6 of 34 studies demonstrated a benefit of TDM adjusted management for efficacy IFD treatment. Data in favor of the use of TDM in pts with proven or probable IFD, in particular non-responding pts with IFD to avoid discontinuation of VCZ treatment was limited (AII). Small data is available for pts <2 ys. Pts aged ≤6 years needed a significantly higher median dose of oral VCZ to maintain therapeutic trough levels compared to older patients (BII). However, there is no clear evidence on how to adjust dosage in pediatric pts with inappropriate drug levels. The oral formulation is recommended for renal failure pts with hemofiltration. Obese adults and pediatric pts show particularly high variability (AII) and are therefore candidates for TDM under treatment with VCZ (AII). Dose adjustment by 50% to 100% has been performed in clinical trials. If the oral dosage is changed, TDM should be repeated after at least 2 days (BIII). There is no data to support dose adaptations of targeted metabolized via CYP3A4 therapies in pts with hematological malignancies during VCZ treatment to reduce DDI. Conclusion: VCZ dosing in hematology pts remains complex in daily clinical practice, in particular in children and obese pts. While there is evidence supporting TDM to reduce toxicity (AI), there is no clear evidence that efficacy outcome is improved by TDM of VCZ for the management of IFD (BII). Subgroups of hematology pts benefit from TDM to avoid either too low or excessively high VCZ levels, respectively (AI).