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Leukotriene Modifiers and Pharmacogenetics

For any given disease, including asthma, there is variability of a given individual's response to a given pharmacotherapy (interindividual variability) and there is variability of a given individual's response to a given therapy on repeated occasions (intraindividual repeatability). Pharmacogenetics is the term applied to the study of the contribution of genetic differences among individuals to the variability in the responses to pharmacotherapy among individuals (186-188). As the response to leukotriene modifiers is not uniform across all asthmatics, and not every asthmatic responds to these medications to the same degree (189), it is hypothesized that an important determinant of responsiveness to these therapies is genetic. Several of the genes involved in the regulation of leukotriene synthesis and degradation have been studied and assessed for functional polymorphic variants that could account for differences in therapeutic responses to these agents. Polymorphisms of the 5-LO promoter gene and the LTC4 synthase gene have been studied and have been determined to play important roles in the response to leukotriene modifier therapy.

For example, Drazen and colleagues (190) postulated that since asthma patients harboring mutant forms of the 5-LO core promoter might have diminished 5-LO gene transcription, their asthma may be less dependent on leukotriene formation, and therefore they may be less sensitive to the antiasthma effects of 5-LO inhibition. To test this hypothesis, they stratified, by genotype at the 5-LO promoter, a cohort of 221 mild-to-moderate asthmatics who had completed a double-blind, randomized, placebo-controlled trial with a 5-LO inhibitor, ABT-761, which is clinically similar to zileuton (190). After 84 days of treatment, the 64 patients with wildtype genotype at the 5-LO core promoter locus who had received treatment with the 5-LO inhibitor had a substantially greater improvement in FEV1 than that in the 10 patients with no wild-type allele at the 5-LO core promoter receiving the same dose of medication (18.8% improvement vs. 1.1% decline p < 0.0001) (Fig. 5). They also had a significantly greater improvement than the 69 patients with the same genotype who received placebo (only 5.1% improvement, p = 0.0037). This was the first demonstration in which genotype at a locus in a gene was of value in prospectively identifying a group of patients with an altered response to treatment and provided a rationale for the pharmacogenetic tailoring of medication regimens to the genetic makeup of the patient receiving treatment. In addition to studies of the 5-LO promoter, polymorphisms of other enzymes in the leukotriene pathway have been examined, including polymorphisms of the LTC4 synthase gene (191). Sampson and colleagues demonstrated that in a small group of asthmatic subjects with variant LTC4 synthase genotypes, administration of the leukotriene receptor antagonist zafirlukast for two weeks resulted in an increase in FEV1 by 9%, while patients with wild-type genotype had a 12% decrease in FEV1 (192). While these results failed to have statistical significance (likely due to the small sample size), the trend in differential response based on LTC4 synthase polymorphisms suggests that this locus, too, may have a role in determining response to asthma therapy. These findings are important as they highlight the fact that in the future, one may be able to

Figure 5 Percent change in FEV1 from baseline in subjects with wild-type genotype at the 5-LO core promoter locus treated with the 5-LO inhibitor ABT-761 or placebo and for patients with no wild-type alleles treated with ABT-761. Source: From Ref. 190.

utilize pharmacogenetics to determine which patients may be responders to these therapies and, perhaps, which individuals may develop particular side effects from these therapies.

Novel Therapies and Indications

Future directions of research regarding leukotriene modifiers will revolve around novel therapies and new indications. An active area of investigation is the search for new medications that target specific areas of the 5-LO cascade. Current research involves the development and clinical evaluation of new 5-LO inhibitors and cysteinyl leukotriene receptor antagonists, as well as PLA2 inhibitors, FLAP inhibitors, and LTB4 receptor antagonists. For instance, the FLAP inhibitor MK-0591 was given to patients with moderately severe asthma who required treatment with inhaled corticosteroids, and those who received 125 mg of the drug twice daily had a significantly greater rise in mean FEVi and peak flow rates compared to those receiving placebo and also had fewer asthma symptoms and no adverse events (193). Similarly, when another FLAP inhibitor, BAYx1005, was given to 67 patients with moderate chronic asthma receiving corticosteroids, there were small but significant increases in FEV1 after four weeks of treatment (194).

These classes of promising drugs may contribute significantly to asthma therapy in the future. While the potential role of these agents is very exciting, so is the potential use of current leukotriene modifiers, which have been shown to cause rapid benefit in the setting of acute asthma in the emergency department (195).

Leukotriene modifiers are currently being prescribed to patients with COPD, rhinosinusitis, and RSV infection. While there might be some theoretical and anecdotal basis for their use in these conditions, there have been no clinical trials to date documenting definitive efficacy or safety in these populations, and no drugs involved in the 5-LO pathway are currently approved for these or other inflammatory conditions. As we learn more about leukotrienes and their functions through further investigation, we will undoubtedly uncover much about the pathobiology of asthma and other inflammatory entities.

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