Singulair Mechanism of Action

Pharmacology: Pharmacodynamics: Montelukast causes potent inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD₄ in asthmatic patients. Doses as low as 5 mg cause substantial blockage of LTD₄-induced bronchoconstriction.
Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.
Clinical studies in adults 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. This was shown in two chronic asthma studies using doses up to 200 mg once daily and in one exercise challenge study using doses up to 50 mg, evaluated at the end of the once-daily dosing interval.
Pharmacokinetics: Absorption: Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10-mg film-coated tablet, the mean peak plasma concentration (C_max) is achieved 3 hours (T_max) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal.
For the 5-mg chewable tablet, the C_max 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, C_max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.
The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The coadministration of applesauce or a standard meal with the oral granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC (1225.7 vs 1223.1 ng·hr/mL with and without applesauce, respectively, and 1191.8 vs 1148.5 ng·hr/mL with and without a standard meal, respectively).
Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable tablet, 5-mg chewable tablet, and 10-mg film-coated tablet were administered without regard to the timing of food ingestion. The safety of MONTELUKAST (SINGULAIR) was also demonstrated in a clinical study in which the 4-mg oral granules 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 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
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 cytochrome P450 3A4, 2C8 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 fecal 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 drug 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 (Child-Pugh score > 9).
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 Pediatric Patients: The plasma concentration profile of montelukast following administration of 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 show that the plasma profiles of the 4-mg oral granule formulation in pediatric patients 6 months to 2 years of age, the 4-mg chewable tablet in pediatric patients 2 to 5 years of age, and the 5-mg chewable tablets in pediatric patients 6 to 14 years of age were similar to the plasma profile of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4-mg chewable tablet in pediatric patients 2 to 5 years of age. The 4-mg oral granule formulation should be used for pediatric patients 6 months to 2 years of age. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.
Drug Interactions: Montelukast 10 mg once daily to pharmacokinetic steady state: did not cause clinically significant changes in the kinetics of an intravenous dose of theophylline; did not change the pharmacokinetic profile of warfarin or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or INR (International Normalized Ratio); did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the plasma concentration profile of terfenadine or its carboxylated metabolite and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily.
Montelukast at doses of ≥ 100 mg daily to pharmacokinetic steady state: did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 μg; did not cause any clinically significant change in plasma profiles of either prednisone and prednisolone following administration of either oral prednisone or intravenous prednisolone.
Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast; no dosage adjustment for MONTELUKAST (SINGULAIR) is recommended (see PRECAUTIONS).