Montezyd 4/Montezyd 5/Montezyd 10 Mechanism of Action

Leukotriene Receptor Antagonist.
Pharmacology: The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids 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 airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. 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 has not been assessed in intranasal challenge studies. The clinical relevance of intranasal challenge studies is unknown.
Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β‑adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.
Pharmacodynamics: Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Montelukast inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.
The effect of Montelukast on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Montelukast, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received Montelukast, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of Montelukast. The relationship between these observations and the clinical benefits of Montelukast noted in the clinical trials is not known.
Pharmacokinetics: Montezyd 4/Montezyd 5: Absorption: For the 5 mg chewable tablet, the Cmax is achieved 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73%. Food does not have a clinically important influence with chronic administration.
For the 4 mg chewable tablet, Cmax is achieved 2 hours after administration in paediatric patients 2 to 5 years of age in the fasted state.
Safety and efficacy were demonstrated in clinical studies where the 4 mg chewable tablet and 5 mg chewable tablet, were administered without regard to the timing of food ingestion.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8 to 11 litres. Studies in rats with radiolabeled Montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours post-dose were minimal in all other tissues.
Metabolism: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and paediatric patients.
In vitro studies using human liver microsomes indicate that cytochrome P450 3A4 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.
Elimination: The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates Montelukast and its metabolites are excreted almost exclusively via the bile.
In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Montelukast are nearly linear for oral doses up to 50 mg. No difference in pharmacokinetics was noted between dosing in the morning or in the evening.
Montezyd 10: Absorption: Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8 to 11 litres. Studies in rats with radiolabeled Montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours post-dose were minimal in all other tissues.
Metabolism: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and paediatric patients. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4 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.
Elimination: The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates Montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Montelukast are nearly linear for oral doses up to 50 mg. No difference in pharmacokinetics was noted between dosing in the morning or in the evening. During once-daily dosing with 10 mg Montelukast, there is little accumulation of the parent medicine in plasma (~14%).
Characteristics in Patients: Gender: The pharmacokinetics of Montelukast are similar in males and females.
Elderly: The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of Montelukast are similar in elderly and younger adults. The plasma half-life of Montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.
Race: Pharmacokinetic differences due to race have not been studied. In clinical studies, there do not appear to be any differences in clinically important effects.
Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Montelukast resulting in approximately 41% higher mean Montelukast area under the plasma concentration curve (AUC) following a single 10 mg dose. The elimination of Montelukast is slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. There are no clinical data in patients with severe hepatic insufficiency.
Renal Insufficiency: Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of Montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.
Adolescents and Paediatric Patients: The plasma concentration profile of Montelukast following the 10 mg film-coated tablet is similar in adolescents ≥15 years old and young adults. The 10 mg film-coated tablet is recommended for use in patients ≥15 years old.
Pharmacokinetic studies using either the chewable tablet or film-coated tablet show that the plasma profile of the 5 mg chewable tablet in paediatric patients 6 to 14 years of age is similar to that of the 10 mg film-coated tablet in adults. In a pharmacokinetic study in paediatric patients 2 to 5 years of age, the plasma profile of the 4 mg chewable tablet was also similar to that of the 10 mg film-coated tablet in adults. The 5 mg chewable tablet should be used in paediatric patients 6 to 14 years of age and the 4 mg chewable tablet in paediatric patients 2 to 5 years of age.