Single dose pharmacokinetics, safety and tolerability of MK‐0476, a new leukotriene D4‐receptor antagonist, in healthy volunteers.

Abstract

acetate is a novel, potent, and specific LTD4-receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK-0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9-subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK-0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK-0476 (20 to 800 mg) the median value of tmax ranged from 2 to 4 h, while the apparent ti,2 value averaged 4 to 5 h. The median tmax value of the 200 mg capsule dose was not significantly different from the median tmax of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate-limiting step for the absorption of MK-0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in Cmax (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK-0476 was given together with a breakfast, suggesting an increase in bioavailability. We conclude that single oral doses of MK-0476 (range 20 to 800 mg) appear to be well tolerated and both formulations (capsule and solution) achieve similar plasma concentrations.

A Population Pharmacokinetic Model for Montelukast Disposition in Adults and Children

“…The pharmacokinetics of montelukast after single-dose oral administration have been extensively studied (11,13,16,25). Most of the data published include routine noncompartmental analysis.…”

“…The clinical pharmacokinetics (PK) of montelukast after oral administration have been studied extensively using conventional noncompartmental pharmacokinetic analyses (11)(12)(13). Montelukast is rapidly absorbed after oral administration and is extensively metabolized followed predominantly by elimination in bile (14).…”

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

“…The safety, tolerability, gender eect, and pharmacokinetic pro®le of oral and intravenous montelukast sodium in healthy volunteers have already been evaluated. 3,4 Results of these studies indicate that montelukast sodium is well tolerated in healthy subjects, the disposition kinetics of montelukast sodium are linear across the therapeutic dose range, and gender has little or no eect on the pharmacokinetics of montelukast.…”

Drugs for the Treatment of Allergic Diseases

“…Pranlukast is one of the most efficacious antiallergic drugs for the treatment of bronchial asthma at present and is expected to reduce the dose of glucocorticoid necessary to control airway inflammation. Similar LT1 cysteinyl leukotriene-receptor antagonists, zafirlukast (18) and montelukast (19), have also been developed after pranlukast and applied clinically in Europe and America. They will be available in Japan in the near future.…”