Montiget Mechanism of Action

Pharmacology: Pharmacodynamics: Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT type-1 (CysLT₁) receptor. Montelukast inhibits physiologic actions of LTD₄ at the CysLT₁ receptor without any agonist activity. 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 CysLT receptors. Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of allergic rhinitis and asthma. The CysLT₁ receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other proinflammatory cells (including eosinophils and certain myeloid stem cells).
Pharmacokinetics: Absorption: Montelukast is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (C_max) is achieved in 3 to 4 hours (T_max). The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal in the morning.
For the 5 mg chewable tablet, the mean C_max is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.
For the 4 mg chewable tablet, the mean C_max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters.
Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.
Excretion: The plasma clearance of montelukast averages 45 mL/min in healthy adults. Montelukast and its metabolites are excreted almost exclusively via the bile. The mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10 mg montelukast, there is little accumulation of the parent drug in plasma (14%).
Special Populations: Hepatic function impairment: In patients with mild to moderate hepatic insufficiency and cirrhosis, metabolism was decreased, resulting in a 41% higher mean AUC. The elimination is prolonged with a mean half-life of 7.4 hours.
Elderly: The plasma half-life of montelukast is slightly longer in elderly patients.
Children: In children 6 to 11 months of age, the systemic exposure and the variability of plasma montelukast concentrations are higher than those observed in adults. Mean AUC (4296 ng•hr/mL) was 60% higher and the mean C_max (667 ng/mL) was 89% higher than those observed in adults. The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3,574 ng•hr/mL was 33% higher and the mean C_max (562 ng/mL) was 60% higher than those observed in adults.