Clinical Course and Risk Factors for Voriconazole-induced Hepatotoxicity

Abstract

Hepatotoxicity associated with administration of voriconazole (VRCZ) is a major treatment-related adverse event and in some cases requires discontinuation of therapy. This study aimed to investigate the clinical course and risk factors for VRCZ-induced hepatotoxicity. Demographic and laboratory data were retrieved retrospectively from the medical records of 66 Japanese patients who underwent VRCZ treatment. VRCZ-induced hepatotoxicity was defined as an abnormal increase in liver function tests. VRCZ-induced hepatotoxicity was observed in 30 patients (45％), with 11 (37％) of these patients needing to discontinue the drug. Most of the events were observed within 1 to 2 weeks after the first dose of VRCZ. Of the liver function tests, an abnormal increase in γ-glutamyl transferase tended to occur earlier than changes in the other tests (ie, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin). Multiple logistic regression analysis showed that the trough concentration of VRCZ was a risk factor for hepatotoxicity (adjusted odds ratio = 2.89, 95％CI 1.49-5.59, P = 0.002). Based on this result, a VRCZ trough concentration < 4 μg/mL was considered to be the target for minimizing the risk of developing hepatotoxicity. After discontinuation of VRCZ in patients who developed hepatotoxicity, every liver enzyme abnormality improved within approximately 1 week.In conclusion, this study shows that VRCZ-induced hepatotoxicity may occur early after the initiation of VRCZ therapy. We therefore recommend appropriate adjustments of the starting dose and frequent liver function tests in patients treated with VRCZ, especially during the first 2 weeks.

Clinical evaluation of an authorized medical equipment based on high performance liquid chromatography for measurement of serum voriconazole concentration

“…However, it needs a certain time (days within a 1 week) to obtain the feedback of the measurement result, then opportunity for the dose optimization will come at more than 10 days after first dose at last. Because median days of therapy for development of voriconazole-induced hepatotoxicity is reportedly 10 days [ 4 ], the outsourcing measurement should be discouraged for maximal safe medication. It means that the measurement in individual hospitals should be encouraged.…”

Case of mycotic cyst caused by Scedosporium apiospermum developed liver dysfunction following administration of voriconazole

“…In Japanese, blood voriconazole concentration should be adjusted to prevent liver dysfunction and neurological symptoms. 4 The standard trough value 5 days after administration is 1-2 lg/mL, and values exceeding 4-5 lg/mL suggest liver dysfunction. 5 Although the blood trough value of our patient was only 1.69 lg/mL, liver impairment reached common terminology criteria for adverse events, grade 2.…”

“…Many improved several weeks after discontinuation of voriconazole. 4 Voriconazole is effective against S. apiospermum, but be on guard for adverse side-effects.…”