Pre-emptive CYP2C19 genotyping and voriconazole exposure in pediatric hematology patients at risk of aspergillosis: an exploratory randomized pilot study with a cost-consequence analysis

Introduction Voriconazole is a first-line therapy for invasive aspergillosis, but its use is complicated by pronounced pharmacokinetic variability, largely driven by CYP2C19 polymorphisms. We aimed to evaluate whether preemptive CYP2C19 genotyping improves early target attainment and clinical management in pediatric hematology patients compared with standard practice. Methods We conducted a pragmatic, randomized, single-blind trial (EudraCT: 2019-000376-41; ClinicalTrials.gov: NCT04238884). Pediatric hematology patients at high risk of aspergillosis were randomized (1:1) to receive either standard weight-based dosing (Control) or preemptive CYP2C19 (*1, *2, *3, *17 alleles) genotype-guided dosing (Experimental). The primary endpoint was the proportion of patients achieving a therapeutic voriconazole trough concentration (Cmin: 1.0–5.0 mg/L) at Day 5 (±1). The analysis was conducted using a modified intention-to-treat approach. Results Thirty-two patients (16 per arm) were evaluated. The experimental arm had a higher proportion of patients achieving the therapeutic range compared to the control arm, but not statistically significant (37.5% vs. 12.5%, p = 0.200). The proportion of patients with subtherapeutic exposure (<1.0 mg/L) was lower in the genotype-guided arm than in the standard-of-care arm (31.3% vs. 68.8%, p = 0.034). Supratherapeutic levels were comparable between groups (25% vs. 18.8%, p > 0.900). An exploratory cost-consequence analysis was associated with a mean difference in direct medical costs of €5,819 per patient in favour of the genotype-guided arm, although this difference was not statistically significant (p = 0.300). Conclusion Preemptive CYP2C19 genotyping was associated with a lower proportion of early subtherapeutic voriconazole exposure compared with standard care, with no signal of increased toxicity. Clinical Trial Registration https://clinicaltrials.gov/study/NCT04238884 ; https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-000376-41/ES , identifier EudraCT: 2019-000376-41; NCT04238884.