PHARMACOKINETICS, BIOAVAILABILITY, AND SAFETY OF MONTELUKAST SODIUM (MK-0476) IN HEALTHY-MALES AND FEMALES

Purpose. The safety, tolerability, and pharmacokinetics of intravenous (i.v.) montelukast sodium (Singulair(TM), MK-0476), and the oral bioa vailability of montelukast sodium in healthy males and healthy females were studied. Methods. This was a two-part study. Part I was a four-p eriod study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Pe riods 1-3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 min utes (Periods 5 and 6, respectively) or injected as a bolus over 2 min utes (Period 7), followed by a 10-mg oral tablet dose of montelukast s odium (Period 8). Plasma samples were collected and analyzed by HPLC. Results. In males (N = 6), as the i.v. dose of montelukast sodium incr eased from 3 to 18 mg, the area under the plasma concentration-time cu rve of montelukast sodium from time 0 to infinity (AUC) increased prop ortionately. The mean values of plasma clearance (CL), steady-state vo lume of distribution (V-ss), plasma terminal half-life (t(1/12)), and mean residence time in the body (MRT(i.v.)) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained e ssentially constant over the i.v. dosage range. Following oral adminis tration of a 10-mg tablet of montelukast sodium, the AUG, maximum plas ma concentration (C-max), time when C-max occurred (T-max), apparent t (1/12), mean absorption time (MAT), and bioavailability (F) of montelu kast sodium averaged 2441 ng . hr/ml, 385 ng/ml, 3.7 hr, 4.9 hr, 3.4 h r, and 66%, respectively. Following i.v. administration of 9 mg of mon telukast sodium to females (N = 6), the values of CL, V-ss, t(1/2), an d MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respective ly. Following oral administration of a 10-mg tablet to females, the me an AUC, C-max, T-max, apparent t(1/2), MAT and F were 2270 ng . hr/ ml , 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These para meter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. Conclusions. The dispos ition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.