Pharmacology: Mechanism of Action: Montelukast sodium is a competitive selective and orally active leukotriene D4 (cysteinyl leukotriene CysLT1) receptor antagonist. The cysteinyl leukotrienes (LTC4, LTD4 and 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. Binding of cysteinyl leukotrienes to leukotriene receptors has been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction and altered cellular activity associated with the inflammatory process, factors that contribute to the signs and symptoms of asthma. Thus, montelukast sodium inhibits physiologic actions of LTD4 at the CysLT1 receptors, without any agonist activity.
Pharmacokinetics: Absorption: Montelukast sodium is rapidly absorbed following oral administration. Peak plasma concentrations of montelukast sodium are achieved in 2-4 hrs after oral administration. The mean oral bioavailability is 64%.
Distribution: Montelukast sodium is >99% bound to plasma proteins. The mean plasma t½ of montelukast sodium ranged from 2.7-5.5 hrs in healthy young adults. The pharmacokinetics of montelukast sodium is nearly linear for oral doses up to 50 mg.
Metabolism: Montelukast sodium is extensively metabolized in the liver by cytochrome P-450 isoenzymes CYP3A4, CYP2A6 and CYP2C9. Therapeutic plasma concentrations of montelukast sodium do not inhibit cytochromes P-450, 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.
Elimination: The plasma clearance of montelukast sodium averages 45 mL/min in healthy adults. Montelukast sodium and its metabolites are excreted principally in the feces via the bile.
Special Populations: Elderly, pediatric, males, females and patients with renal insufficiency have similar plasma pharmacokinetic profiles as young adults.
Hepatic Insuficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism and prolonged elimination t½ of montelukast sodium resulting in 41% higher mean area under the plasma concentration curve (AUC) following a single 10 mg dose. No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency.
Pediatric patients: In children 6-11 months, the systemic exposure to montelukast and the variability of plasma montelukast concentrations were higher than those observed in adults. Safety and tolerability of montelukast in a single-dose pharmacokinetic study in children 6-23 months were similar to that of patients ≥2 years.