Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations

M. A. Encalada Ventura, M. J. P. van Wanrooy, L. F. R. Span, Michael G. G. Rodgers, E. R. van den Heuvel, D. R. A. Uges, T. S. van der Werf, J. G. W. Kosterink, J. W. C. Alffenaar*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

41 Citations (Scopus)
285 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2727-2731
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number5
DOIs
Publication statusPublished - May-2016

Keywords

  • DRUG-METABOLIZING-ENZYMES
  • C-REACTIVE PROTEIN
  • INTRAVENOUS VORICONAZOLE
  • CYP2C19 GENOTYPE
  • ANTIFUNGAL AGENT
  • PHARMACOKINETICS
  • SAFETY
  • VARIABILITY
  • CANCER
  • ASPERGILLOSIS

Cite this