Inflammation influences variability of variconazole trough concentrations

Jairia Dela Cruz
04 Dec 2017

Voriconazole serum concentrations during treatment of chronic pulmonary aspergillosis (CPA) appear to vary widely in relation to C-reactive protein (CRP), according to a study, suggesting that inflammation may reduce drug clearance.

“Therefore, multiple measurements of trough concentrations are recommended even with the same dose,” researchers said.

Researchers had performed a retrospective chart review involving 218 serum samples from 69 patients (median age 71 years; 75 percent female) treated for CPA. The most common underlying diseases were old pulmonary tuberculosis (30 percent), nontuberculous mycobacteriosis (25 percent) and chronic obstructive pulmonary disease (19 percent). Repeated voriconazole trough concentration measurements were taken with the same dosage.

Results, which were presented at the 22nd Congress of the Asian Pacific Society of Respirology (APSR 2017), revealed that 13 patients (19 percent) exhibited varied trough levels of 3 μg/ml. The median variability of voriconazole concentration with the same dose in a single patient was 1.83μg/ml (range, 0 to 10.94). [APSR 2017, abstract AP309]

There was a positive association between voriconazole concentration and CRP levels, and this was significant on both simple and multiple linear regression analyses (p<0.0001 for both).

The present finding is consistent with that of previous studies demonstrating inflammation as one of the factors that might influence voriconazole pharmacokinetics, researchers said. It was reported that drug concentration increased by 0.015 mg/L for every 0.1-mg/dL increase in CRP level, with a CRP of 4.7 mg/dL useful for predicting voriconazole toxicity. [Antimicrob Agents Chemother 2014;58:7098-7101; Clin Chim Acta 2015;441:127-32]

Researchers highlighted the viability of CRP, which is easily measured in clinical practice, for assessing voriconazole trough concentration variation. Additionally, it is important to measure the drug concentration even after CRP levels decrease, as long-term exposure to voriconazole at doses less than or equal to the minimum effective concentration has the potential to induce resistance. [Clin Microbiol Infect 2016;22:570.e1-9]

The positive association between severe inflammation and voriconazole trough concentrations may be explained by a downregulation of CYP isoenzymes as a result of inflammatory stimuli, leading to reduced metabolism of the drug. [Clin Pharmacol Ther 2009;85:434–438]

Used in the first-line treatment of CPA, voriconazole in clinical practice exhibits a large variability in concentrations not only between patients but also within individual patients over time. As a result, therapeutic drug monitoring has been recommended.

The Infectious Diseases Society of America guidelines cite maintaining voriconazole concentrations in the >1 to 1.5 μg/ml to <5 to 6 μg/ml range to ensure efficacy and minimize toxicity. [Clin Infect Dis 2016;63:e1-e60]

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