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.

CYP2C19 polymorphism is the main genetic driver of voriconazole pharmacokinetic variability, with a target trough concentration between 1.0 and 5.0 mg/L.

Voriconazole, first-line therapy for invasive aspergillosis, shows marked pharmacokinetic variability largely driven by CYP2C19 polymorphism. This pragmatic single-blind randomised trial (NCT04238884) allocated 32 paediatric haematology patients at high risk of aspergillosis, 16 per arm, to standard weight-based dosing or to dosing guided by pre-emptive CYP2C19 genotyping covering alleles 1, 2, 3 and 17. The primary endpoint, the proportion of patients reaching a target trough concentration of 1.0 to 5.0 mg/L at day 5, was not significantly improved (37.5% versus 12.5%, p = 0.200). Subtherapeutic exposure below 1.0 mg/L was however less frequent in the genotype-guided arm (31.3% versus 68.8%, p = 0.034), with no excess of supratherapeutic levels (25% versus 18.8%, p > 0.900). An exploratory cost-consequence analysis found a mean difference in direct medical costs of EUR 5,819 per patient favouring the genotype-guided arm, not statistically significant (p = 0.300).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The primary endpoint is negative and must be presented as such: this is a 32-patient pilot, powered to explore rather than to conclude. The usable signal is the halving of early subtherapeutic exposure, consistent with voriconazole pharmacology and without visible toxicity trade-off. The cost difference of EUR 5,819 per patient must not be quoted as a demonstrated saving, with a p value of 0.300 in 32 patients; and whatever the genotype, therapeutic drug monitoring remains the last line of safety.

Analysis by Dr Thibaut Benquey