title: Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations.
abstract: Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Encalada Ventura
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: M J P
authors.initials: MJ
authors.lastname: van Wanrooy
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, The Netherlands.
authors.forename: L F R
authors.initials: LF
authors.lastname: Span
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Surgical Intensive Care, Groningen, The Netherlands.
authors.forename: M G G
authors.initials: MG
authors.lastname: Rodgers
authors.affiliation: Eindhoven University of Technology, Department of Mathematics and Computer Science, Eindhoven, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: van den Heuvel
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: D R A
authors.initials: DR
authors.lastname: Uges
authors.affiliation: University of Groningen, University Medical Center Groningen, Departments of Internal Medicine and Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: T S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D065819:Voriconazole / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D002097:C-Reactive Protein; D065819:Voriconazole