A retrospective analysis of patient-specific factors on voriconazole clearance

Abstract

Background: Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. We investigated the relationships of voriconazole concentration with patient-specific variables and concomitant medication to identify clinical factors affecting voriconazole clearance.

Methods: A retrospective chart review of voriconazole trough concentration, laboratory data, and concomitant medication in patients was performed. The concentration/dose ratio (C/D-ratio) was assessed as a surrogate marker of total clearance by dividing voriconazole concentration by daily dose per kg of body weight.

Results: A total of 77 samples from 63 patients were obtained. In multiple linear regression analysis, increased C-reactive protein (CRP) level (p < 0.05) and decreased albumin (Alb) level (p < 0.05) were associated with significantly increased C/D-ratio of voriconazole, and coadministration with a glucocorticoid was associated with significantly (p < 0.05) decreased C/D-ratio of voriconazole (adjusted r (2) = 0.31). Regarding CRP and Alb, receiver operating characteristic curve analysis indicated that increased CRP level and decreased Alb level were significant predictors of toxic trough concentration of voriconazole. For CRP, area under the curve (AUC) and cutoff value were 0.71 (95 % confidence interval (CI), 0.57-0.86, p < 0.01) and 4.7 mg/dl, respectively. For Alb, AUC and cutoff value were 0.68 (95 % CI, 0.53-0.82, p < 0.05) and 2.7 g/dl, respectively. A significant difference was seen in voriconazole trough concentration between patients with hepatotoxicity and those without (5.69 μg/ml vs 3.0 μg/ml, p < 0.001).

Conclusion: Coadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance. We propose that early measurement of voriconazole concentration before the plateau phase will lead to avoidance of a toxic voriconazole level in patients with elevated CRP level and hypoalbuminemia, although further studies are needed to confirm our findings.

Keywords: Drug interaction; Inflammation; Pharmacokinetics; Therapeutic drug monitoring; Voriconazole.

Fig. 1

Relationship between voriconazole dosages per patient weight and voriconazole trough concentration. Each point represents a measurement. The linear regression curve is presented with coefficient of determination (r²)

Fig. 2

Comparison of mean voriconazole concentration/dose ratio. A scatter plot of voriconazole concentration/dose ratio from 77 samples for 63 patients without coadministration of glucocorticoid (n = 49) and with coadministration of glucocorticoid (n = 28). Solid line means mean

Fig. 3

Receiver operating characteristic (ROC) curves for predicting risk of toxic voriconazole level on the basis of CRP (a) and Alb (b); relationships of toxic voriconazole level with CRP and Alb (c). The true-positive rate represents the proportion of true positives that are correctly classified as positive. The false-positive rate represents the proportion of true negatives that are incorrectly classified as positive. True-positive rate = true positives/(true positives + false negatives). False-positive rate = false positives/(false positives + true negatives). Closed circles represent patients with toxic voriconazole level and open circles represent patients without toxic voriconazole level. 95 % CI, 95 % confidence interval

Fig. 4

Relationships between voriconazole concentration and toxicities. A scatter plot of voriconazole concentrations from all 63 patients. Closed circles represent patients with toxicity and open circles represent patients without toxicity. Closed diamond represents patients with Grade 3 hepatotoxicity. Solid line means mean. One patient was not assessed for visual disturbance and neurotoxicity because of the administration of a sedative. Four patients were not assessed for hepatotoxicity because of liver dysfunction due to primary disease. A significant difference was seen in voriconazole mean trough concentration between patients with grade 2-3 hepatotoxicity and those without: 5.69 (SD 2.27) vs. 3.0 (SD 2.07), p < 0.001. No significant difference was seen in voriconazole mean trough concentration between patients with other adverse events and those without: visual disturbance - 3.48 (SD 1.79) vs. 3.44 (SD 2.7), p = 0.94; neurotoxicity - 4.2 (SD 2.85) vs. 3.27 (SD 2.11), p = 0.18