Aerokids Mechanism of Action

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, leukotriene receptor antagonists.
Pharmacology: Pharmacodynamics: The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT₁) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT₁ receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD₄ at doses as low as 5 mg. Bronchoconstriction was observed within 2 hours of oral administration. The bronchoconstriction effect caused by a β-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.
In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant improvements in the morning forced expiratory volume in one second (FEV₁) (10.4% vs. 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs. 3.3 L/min change from baseline), and a significant decrease in total β-agonist use (-26.1% vs. -4.6% change from baseline). Improvement in patient-reported daytime and night-time asthma symptoms scores was significantly better than placebo.
Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs. beclomethasone, respectively for FEV₁: 5.43% vs. 1.04%; β-agonist use: -8.70% vs. 2.64%). Compared with inhaled beclomethasone (200 µg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided a greater average treatment effect (% change from baseline for montelukast vs. beclomethasone, respectively for FEV₁: 7.49% vs. 13.3%; β-agonist use: -28.28% vs. -43.89%). However, compared with beclomethasone, a high percentage of patients treated with montelukast achieved similar clinical responses (i.e. 50% of patients treated with beclomethasone achieved improvement in FEV₁ of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).
A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis. In this study, montelukast 10-mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptom score, compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhoea, sneezing, nasal itching) and the Night-time Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and night-time awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not the primary objective in this study.
In an 8-week study in paediatric patients (6 to 14 years of age), montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV₁ 8.71% vs. 4.16% change from baseline; AM PEFR 27.9 L/min vs. 17.8 L/min change from baseline) and decreased "as-needed" β-agonist use (-11.7% vs. +8.2% change from baseline).
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV₁, 22.33% for montelukast vs. 32.40% for placebo; time to recovery to within 5% of baseline FEV₁, 44.22 min vs. 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV₁, 18.27% vs. 26.11%; time to recovery to within 5% of baseline FEV₁, 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.
In acetylsalicylic acid-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma management (FEV₁ 8.55% vs. -1.74% change from baseline and decrease in total β-agonist use -27.78% vs. 2.09% change from baseline).
Pharmacokinetics: Absoprtion: For the 5-mg chewable tablet, the C_max is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 L. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material after 24 hours were minimal in all other tissues.
Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination: The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in the urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in patients: No dose adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.
Toxicology: Preclinical safety data: In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at doses which provided >17-fold the systemic exposure seen at the clinical dose. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pub body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m² and 30,000 mg/m² in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.