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A retrospective analysis of patient-specific factors on voriconazole clearance.

Dote S, Sawai M, Nozaki A, Naruhashi K, Kobayashi Y, Nakanishi H - J Pharm Health Care Sci (2016)

Bottom Line: 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.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).Coadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Kyoto-Katsura Hospital, 17 Yamadahirao-cho, Nishikyo-ku, Kyoto 615-8256 Japan.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig4: 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

Mentions: Incidence of hepatotoxicity, visual disturbance, and neurotoxicity were 20.3, 43.5, and 22.6 %, respectively. Twelve episodes of hepatotoxicity were observed: grade 2, six; grade 3, six. Summary of hepatotoxicity were: grade 2 elevation of ALT, one; of ALP, two; of γGTP, four; grade 3 elevation of ALT, one; of ALP, two; of γGTP, six. The voriconazole trough concentration were significantly higher in patients with grade 2–3 hepatotoxicity than in patients without, whereas no significant difference was seen in visual disturbance and neurotoxicity (Fig. 4).Fig. 4


A retrospective analysis of patient-specific factors on voriconazole clearance.

Dote S, Sawai M, Nozaki A, Naruhashi K, Kobayashi Y, Nakanishi H - J Pharm Health Care Sci (2016)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835838&req=5

Fig4: 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
Mentions: Incidence of hepatotoxicity, visual disturbance, and neurotoxicity were 20.3, 43.5, and 22.6 %, respectively. Twelve episodes of hepatotoxicity were observed: grade 2, six; grade 3, six. Summary of hepatotoxicity were: grade 2 elevation of ALT, one; of ALP, two; of γGTP, four; grade 3 elevation of ALT, one; of ALP, two; of γGTP, six. The voriconazole trough concentration were significantly higher in patients with grade 2–3 hepatotoxicity than in patients without, whereas no significant difference was seen in visual disturbance and neurotoxicity (Fig. 4).Fig. 4

Bottom Line: 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.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).Coadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Kyoto-Katsura Hospital, 17 Yamadahirao-cho, Nishikyo-ku, Kyoto 615-8256 Japan.

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.

No MeSH data available.


Related in: MedlinePlus