Josefine Schulz1, Robin Michelet1, Markus Zeitlinger2, Gerd Mikus1,3, Charlotte Kloft4. 1. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169, Berlin, Germany. 2. Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. 3. Department Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. 4. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169, Berlin, Germany. charlotte.kloft@fu-berlin.de.
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.
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.
Authors: Thomas J Walsh; Elias J Anaissie; David W Denning; Raoul Herbrecht; Dimitrios P Kontoyiannis; Kieren A Marr; Vicki A Morrison; Brahm H Segal; William J Steinbach; David A Stevens; Jo-Anne van Burik; John R Wingard; Thomas F Patterson Journal: Clin Infect Dis Date: 2008-02-01 Impact factor: 9.079
Authors: Ruth Van Daele; Isabel Spriet; Joost Wauters; Johan Maertens; Toine Mercier; Sam Van Hecke; Roger Brüggemann Journal: Med Mycol Date: 2019-06-01 Impact factor: 4.076
Authors: A Warris; T Lehrnbecher; E Roilides; E Castagnola; R J M Brüggemann; A H Groll Journal: Clin Microbiol Infect Date: 2019-05-31 Impact factor: 8.067
Authors: Issam S Hamadeh; Kenneth P Klinker; Samuel J Borgert; Ashley I Richards; Wenhui Li; Naveen Mangal; John W Hiemenz; Stephan Schmidt; Taimour Y Langaee; Charles A Peloquin; Julie A Johnson; Larisa H Cavallari Journal: Pharmacogenet Genomics Date: 2017-05 Impact factor: 2.089
Authors: A J Ullmann; J M Aguado; S Arikan-Akdagli; D W Denning; A H Groll; K Lagrou; C Lass-Flörl; R E Lewis; P Munoz; P E Verweij; A Warris; F Ader; M Akova; M C Arendrup; R A Barnes; C Beigelman-Aubry; S Blot; E Bouza; R J M Brüggemann; D Buchheidt; J Cadranel; E Castagnola; A Chakrabarti; M Cuenca-Estrella; G Dimopoulos; J Fortun; J-P Gangneux; J Garbino; W J Heinz; R Herbrecht; C P Heussel; C C Kibbler; N Klimko; B J Kullberg; C Lange; T Lehrnbecher; J Löffler; O Lortholary; J Maertens; O Marchetti; J F Meis; L Pagano; P Ribaud; M Richardson; E Roilides; M Ruhnke; M Sanguinetti; D C Sheppard; J Sinkó; A Skiada; M J G T Vehreschild; C Viscoli; O A Cornely Journal: Clin Microbiol Infect Date: 2018-03-12 Impact factor: 8.067