Abstract
Objective: Zileuton is a 5-lipoxygenase inhibitor approved by the US FDA in 1996 for the treatment of asthma in adults and children. During phase II/III clinical trials, zileuton was generally well tolerated, although elevations in ALT and AST levels were noted in some patients, and a single treated patient developed hepatocellular jaundice. To more fully characterise the hepatic effects of zileuton, and to establish appropriate monitoring guidelines, a 12-month open-label, safety surveillance study was conducted prior to FDA approval.
Patients and methods: In this study, 2458 patients with asthma received zileuton 600mg four times daily in addition to usual asthma care, and 489 patients were treated with usual asthma care only. All patients had their liver biochemistry checked monthly for the first 5 months, and at months 7, 10 and 12 thereafter.
Results: A total of 109 patients (4.4%) receiving zileuton treatment had elevations in ALT levels to ≥3 × the upper limit of normal (ULN), including 31 patients (1.3%) who had levels elevated to ≥8 × ULN, compared with 5 of 480 patients in the usual care alone group (1.0%) who had levels elevated to ≥3 × ULN, of whom 1 (0.2%) had levels elevated to ≥8 × ULN. Elevations in ALT levels were generally not associated with increases in alkaline phosphatase and/or total bilirubin levels. Therefore, the hepatic injury was predominantly hepatocellular. The majority of elevations in ALT level to ≥3 × ULN (64.2%) in the zileuton-treated group occurred within the first 3 months of treatment. There was no correlation between the time of onset of ALT level elevation and the height of the peak ALT level observed. There was no overall difference in the occurrence of elevations in ALT level to ≥3 × ULN between men (4.5%) and women (4.7%), but more women than men experienced an ALT level ≥8 × ULN (1.8% vs 0.5%). Women aged ≥65 years appeared to be at higher risk of elevated ALT levels than those aged <65 years (a rate of 10.1% compared with 4.1%). Patients who experienced ALT levels of ≥3 × ULN but <5 × ULN were allowed to remain on treatment and 52.5% of these patients were able to continue zileuton therapy and experienced resolution of the elevation (a reduction in level to <2 × ULN). In each of the patients who discontinued treatment because of elevated ALT levels, the ALT level returned towards baseline, with a mean time to resolution (defined as a reduction in levels to <2 × ULN) of 4 weeks. No patient in this study developed clinically apparent jaundice or liver failure. Two patients (0.1%) experienced total bilirubin levels ≥1.5 × ULN in association with serum ALT levels exceeding 3 × ULN.
Conclusions: This study established that liver chemistry monitoring is most effective in detecting elevation of ALT levels during the first 3 months of zileuton therapy and that with appropriate monitoring the risk of irreversible liver injury appears to be low.
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1 The use of trade names is for product identification purposes only and does not imply endorsement.
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Acknowledgements
This study was funded by a grant from Abbott Laboratories, North Chicago, Illinois. Abbott Laboratories was responsible for the design and conduct of the study, and for the analysis and reporting of the results. Dr Watkins has acted as a consultant for Abbott Laboratories and Critical Therapeutics Inc. regarding zileuton, but has not received compensation for the preparation of this manuscript. Dr Dube was employed by Abbott Laboratories at the time this study was conducted, is currently acting as a consultant for Critical Therapeutics Inc. and has received stock options from Abbott Laboratories and Critical Therapeutics Inc. Dr Walton-Bowen is currently an employee of and has received stock options from Critical Therapeutics Inc. Drs Cameron and Kasten have no conflicts of interest that are directly relevant to the content of this study. The authors thank Drs Willis, C Maddrey and Steven Schenker for their critical review of this manuscript.
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Watkins, P.B., Dube, L.M., Walton-Bowen, K. et al. Clinical Pattern of Zileuton-Associated Liver Injury. Drug-Safety 30, 805–815 (2007). https://doi.org/10.2165/00002018-200730090-00006
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DOI: https://doi.org/10.2165/00002018-200730090-00006