Page 371 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 357

to aspirin or its metabolites and because it is produced by any of Fcε-R2 receptors) on dendritic cells, basophils, mast cells, and
the NSAIDs that target COX-1, AERD is thought to result from other inflammatory cells, omalizumab inhibits the binding of IgE
inhibition of prostaglandin synthetase (cyclooxygenase), shift- but does not activate IgE already bound to its receptor and thus
ing arachidonic acid metabolism from the prostaglandin to the does not provoke mast cell degranulation.
leukotriene pathway, especially in platelets adherent to circulating Omalizumab’s use is restricted to patients with severe asthma
neutrophils. Support for this idea was provided by the demon- and evidence of allergic sensitization, and the dose administered is
stration that leukotriene pathway inhibitors impressively reduce adjusted for total IgE level and body weight. Administered by sub-
the response to aspirin challenge and improve overall control of cutaneous injection every 2–4 weeks to asthmatic patients, it low-
asthma on a day-to-day basis. ers free plasma IgE to undetectable levels and significantly reduces
Of these agents, montelukast is by far the most prescribed, the magnitude of both early and late bronchospastic responses to
because it may be taken without regard to meals, is taken once antigen challenge. Omalizumab’s most important clinical effect is
daily, and does not require periodic monitoring of liver func- reduction in the frequency and severity of asthma exacerbations,
tion, as zileuton does. Although not considered first-line therapy, while enabling a reduction in corticosteroid requirements. Com-
the leukotriene-modifying agents are sometimes given in lieu of bined analysis of several clinical trials has shown that the patients
inhaled corticosteroids for mild asthma when prescription of an most likely to respond are those with a history of repeated exac-
ICS meets patient resistance. The receptor antagonists have little erbations, a high requirement for corticosteroid treatment, and
toxicity. Early reports of Churg-Strauss syndrome (a systemic vas- poor pulmonary function. Similarly, the exacerbations most often
culitis accompanied by worsening asthma, pulmonary infiltrates, prevented are the most severe; omalizumab treatment reduced
and eosinophilia) appear to have been coincidental, with the exacerbations requiring hospitalization by 88%. Because exacer-
syndrome unmasked by the reduction in prednisone dosage made bations drive so much of the direct and indirect costs of asthma,
possible by the addition of zafirlukast or montelukast. these benefits can justify omalizumab’s high cost.
The addition of omalizumab to standard, guideline-based
TARGETED (MONOCLONAL ANTIBODY) therapy for asthmatic inner-city children and adolescents in early
summer significantly improved overall asthma control, reduced
THERAPY the need for other medications, and nearly eliminated the autum-
nal peak in exacerbations. Omalizumab has also been proven
As the pathophysiologic mechanisms responsible for asthma have effective as a treatment for chronic recurrent urticaria (for which
become better understood, anti-inflammatory therapy targeting the drug is now approved) and for peanut allergy.
specific inflammatory pathways has been developed. Specifically,
monoclonal antibodies targeting IgE and IL-5 have been brought
to market, and an antibody targeting the receptor for IL-4 and Anti-IL-5 Therapy
IL-13 is under development (Table 20–1). T2 cells secrete IL-5 as a pro-eosinophilic cytokine that results
in eosinophilic airway inflammation. Although not central to
Anti-IgE Monoclonal Antibodies the mechanisms of asthma in all patients, a substantial propor-
tion of patients with severe asthma have airway and peripheral
The monoclonal antibody omalizumab was raised in mice and eosinophilia driven by up-regulation of IL-5-secreting T2 lym-
then humanized, making it less likely to cause sensitization when phocytes. Two humanized monoclonal antibodies targeting IL-5,
given to human subjects (see Chapter 55). Because its specific mepolizumab and reslizumab, and another targeting the IL-5
target is the portion of IgE that binds to its receptors (Fcε-R1 and
receptor, benralizumab, have recently been developed for the
treatment of eosinophilic asthma. Clinical trials with these drugs
have shown them to be effective in preventing exacerbations in
TABLE 20–1 Monoclonal antibodies for use in asthmatic patients with peripheral eosinophilia, leading to their
asthma. 1 approval as add-on, maintenance therapy of severe asthma in
patients with an eosinophilic phenotype.
Antibody Name Isotype Target
Like omalizumab, reslizumab carries a small (0.3%) risk of
Omalizumab Humanized IgG1 IgE anaphylaxis, and a period of observation following infusion is
Mepolizumab Humanized IgG1 IL-5 recommended. Mepolizumab, although not associated with ana-
Benralizumab Humanized IgG1 IL-5 receptor phylaxis, has resulted in reports of hypersensitivity. In addition,
reactivation of herpes zoster has been reported in some patients
Reslizumab Humanized IgG4 IL-5
who received mepolizumab.
Lebrikizumab Humanized IgG4 IL-13 (IL-4 receptor- Clinical trials of dupilumab (an antibody directed against the
binding epitope)
IL-4α co-receptor for both IL-4 and IL-13; not yet approved)
GSK679586 Humanized IgG1 IL-13 receptors α1, α2
have shown it to reduce exacerbation frequency and improve
Tralokinumab Humanized IgG4 IL-13 receptors α1, α2 measures of asthma control in patients with and without systemic
Dupilumab Humanized IgG4 IL-4 receptor eosinophilia and, further, to markedly reduce the severity of aller-
1 gic dermatitis.
Approved or in phase 2 or 3 clinical trials.