Microdialysis of Voriconazole and its N-Oxide Metabolite: Amalgamating Knowledge of Distribution and Metabolism Processes in Humans

Purpose Voriconazole is an essential antifungal drug whose complex pharmacokinetics with high interindividual variability impedes effective and safe therapy. By application of the minimally-invasive sampling technique microdialysis, interstitial space fluid (ISF) concentrations of VRC and its potentially toxic N-oxide metabolite (NO) were assessed to evaluate target-site exposure for further elucidating VRC pharmacokinetics. Methods Plasma and ISF samples of a clinical trial with an approved VRC dosing regimen were analyzed for VRC and NO concentrations. Concentration-time profiles, exposure assessed as area-under-the-curve (AUC) and metabolic ratios of four healthy adults in plasma and ISF were evaluated regarding the impact of multiple dosing and CYP2C19 genotype. Results VRC and NO revealed distribution into ISF with AUC values being <= 2.82- and 17.7-fold lower compared to plasma, respectively. Intraindividual variability of metabolic ratios was largest after the first VRC dose administration while interindividual variability increased with multiple dosing. The CYP2C19 genotype influenced interindividual differences with a maximum 6- and 24-fold larger AUC(NO)/AUC(VRC) ratio between the intermediate and rapid metabolizer in plasma and ISF, respectively. VRC metabolism was saturated/auto-inhibited indicated by substantially decreasing metabolic concentration ratios with increasing VRC concentrations and after multiple dosing. Conclusion The feasibility of the simultaneous microdialysis of VRC and NO in vivo was demonstrated and provided new quantitative insights by leveraging distribution and metabolism processes of VRC in humans. The exploratory analysis suggested substantial dissimilarities of VRC and NO pharmacokinetics in plasma and ISF. Ultimately, a thorough understanding of target-site pharmacokinetics might contribute to the optimization of personalized VRC dosing regimens.

Automated summary

This study used microdialysis to assess the concentration of voriconazole (VRC) and its metabolite (NO) in the interstitial space fluid (ISF), in order to evaluate the drug's exposure at the target site and further understand its pharmacokinetics. The results showed that VRC and NO were distributed into the ISF, but at lower concentrations compared to plasma. The variability of metabolic ratios was influenced by multiple dosing and the CYP2C19 genotype. The study also revealed the saturation/auto-inhibition of VRC metabolism.