Microdialysis of Drug and Drug Metabolite: a Comprehensive In Vitro Analysis for Voriconazole and Voriconazole N-oxide

Abstract

Purpose: Voriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic N-oxide metabolite (NO) was performed.

Methods: The feasibility of simultaneous microdialysis of VRC and NO was explored in vitro by investigating the relative recovery (RR) of both compounds in the absence and presence of the other. The dependency of RR on compound combination, concentration, microdialysis catheter and study day was evaluated and quantified by linear mixed-effects modeling.

Results: Median RR of VRC and NO during individual microdialysis were high (87.6% and 91.1%). During simultaneous microdialysis of VRC and NO, median RR did not change (87.9% and 91.1%). The linear mixed-effects model confirmed the absence of significant differences between RR of VRC and NO during individual and simultaneous microdialysis as well as between the two compounds (p > 0.05). No concentration dependency of RR was found (p = 0.284). The study day was the main source of variability (46.3%) while the microdialysis catheter only had a minor effect (4.33%). VRC retrodialysis proved feasible as catheter calibration for both compounds.

Conclusion: These in vitro microdialysis results encourage the application of microdialysis in clinical trials to assess target-site concentrations of VRC and NO. This can support the generation of a coherent understanding of VRC pharmacokinetics and its sources of variability. Ultimately, a better understanding of human VRC pharmacokinetics might contribute to the development of personalized dosing strategies.

Keywords: drug metabolism; exposure; microdialysis; pharmacokinetics; target site; voriconazole.

Fig. 1

Experimental procedure and sampling schedule for the determination of relative recovery of voriconazole (VRC) and its N-oxide metabolite (NO) in a validated in vitro microdialysis system including retrodialysis. Times are given relatively to the start of recovery investigations and start of retrodialysis, respectively.

Fig. 2

In vitro relative recoveries in percent of voriconazole (left panels) and its N-oxide metabolite (right panels) in dependency of the nominal concentration (a), the microdialysis catheter used (b) and the study day (c). The boxes represent the interquartile ranges (IQR) including the respective median of all data points as a bold line. The upper whiskers extend to the largest value but no further than 1.5 * IQR, the lower whiskers extend to the smallest value at most 1.5 * IQR. Individual data points of relative recovery are overlaid (n = 114 for voriconazole and n = 85 for voriconazole N-oxide) as determined from individual microdialysis concentrations and mean concentrations determined in catheter-surrounding medium.

Fig. 3

In vitro relative recovery of voriconazole (VRC, A) and voriconazole N-oxide (NO, B) in percent in the absence (left panel) and presence (right panel) of the respective other.