Development of a dosing algorithm integrating pharmacogenetic markers and inflammation for individualization of initial voriconazole maintenance doses.

CYP2C19

Voriconazole exposure determined by CYP2C19 metaboliser status and by inflammation-driven phenoconversion, which lowers cytochrome activity.

This multicentre retrospective study aimed to build a dosing algorithm for initial voriconazole maintenance doses integrating several determinants of trough concentration. Data from six published studies and seven routine laboratories formed the building cohort (977 trough concentrations in 277 adult patients), with external validation in an independent cohort (47 troughs in 33 patients). The retained mixed-effects model combines daily dose, CYP2C19 genotype and C-reactive protein, enriched by age and underlying disease. It reached an R² of 0.69 but underestimated low troughs and overestimated high ones; the derived formula was embedded in a spreadsheet whose benefit is to be assessed in a prospective pilot study.

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

The value of this algorithm is that it handles genotype and inflammation together, acknowledging that in a febrile haematology patient the predicted CYP2C19 phenotype is not the actual one. That is the right framing of phenoconversion, rarely operationalised in prescribing-support tools. But an R² of 0.69 with bias at both ends of the spectrum means the algorithm errs exactly where dose matters most — neurotoxic overexposure and underexposure — and external validation in 33 patients is too thin to settle the question: for now it does not replace therapeutic drug monitoring, it only helps choose the first dose.

Analysis by Dr Thibaut Benquey