Analysis of factors influencing the relationship between voriconazole plasma concentrations and adverse effects in a paediatric population

Aims: The influence of CYP2C19 polymorphisms on voriconazole plasma concentrations is recognized, but its extent, other contributing factors and risks for adverse reactions remain under-explored. Methods: This study focused on Japanese paediatric patients recruited between 2020 and 2022 treated with voriconazole. We specifically investigated the occurrence of cholestasis and thrombocytopenia as adverse reactions of voriconazole. Voriconazole plasma levels were modelled in a previous study using a population pharmacokinetics approach. Missing values were estimated with a Bayesian method in Phoenix NLME. We analysed CYP2C19*2, CYP2C19*3 and CYP2C19*17. Clinical and laboratory data were collected before and after voriconazole treatment. Results: Among the 60 patients (mean age: 6.5 years; 53.3% male), 38 had haematological malignancies, 18 inborn errors of immunity, 2 solid tumours and 2 other diseases. Adverse reactions occurred in 12 patients. The voriconazole plasma concentrations were significantly higher in those experiencing these adverse reactions (mean normalized concentrations: 0.66 in cases vs. −0.16 in controls, P =.025), with a trend towards higher concentrations in carriers of the CYP2C19*2 or *3 alleles (mean normalized concentrations: 0.98 in carrier cases vs. 0.016 in noncarrier cases, P =.14). A predictive model for voriconazole concentrations, incorporating carriership of CYP2C19*2 or *3, C-reactive protein levels, and platelet counts, showed a summed variance explained of 23.6% with the variance attributable to CYP2C19*2 or *3 carrier status alone was 2.6%. Including carrier status improved the area under the receiver operating characteristic curve for predicting adverse reactions to 0.70. Conclusions: Our findings underscore the role of the CYP2C19 polymorphism in voriconazole-induced thrombocytopenia and cholestasis.