Louise M. Dubé

Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.

Clinical Pattern of Zileuton- Associated Liver Injury Results of a 12-Month Study in Patients with Chronic Asthma

AbstractObjective: 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.

Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study

BACKGROUND A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. OBJECTIVE To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. METHODS Patients with moderate asthma treated with short-acting beta-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n = 206); placebo CR, twice daily (n = 203); zileuton immediate-release (IR), 600 mg 4 times daily (n = 101); or placebo IR, 4 times daily (n = 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). RESULTS Improvement in trough FEV1 was observed after 2 weeks of treatment (P = .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P = .02). A significant decline in beta-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR-treated patients (2.5%) vs 1 placebo CR-treated patient (0.5%). CONCLUSIONS Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo).

The Safety and Efficacy of Zileuton Controlled-Release Tablets as Adjunctive Therapy to Usual Care in the Treatment of Moderate Persistent Asthma: A 6-Month Randomized Controlled Study

This study was conducted to assess the safety and efficacy of zileuton controlled release [CR] 1,200 mg BID added to usual care (UC) in 926 patients with moderate asthma (619 patients randomized to zileuton CR and 307 to placebo). Sustained improvements in AM and PM peak expiratory flow (PEF) were observed in the zileuton CR group compared to placebo. The adverse event profile was similar in the two treatment groups. Eleven patients (1.8%) receiving zileuton CR and 2 (0.7%) receiving placebo experienced elevations of alanine aminotransferase (ALT) ≥ 3X the upper limit of normal (ULN). These elevations typically occurred (81.8%) during the first 3 months of exposure and most resolved within 21 days after discontinuation.