PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

✍ Scribed by Haiyung Cheng; William J. Polvino; David Sciberras; L. Yogendran; Kristine A. Cerchio; Karen Christie; Timothy V. Olah; Debra McLoughlin; Ian James; J. Douglas Rogers

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 429 KB
• Volume: 17
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199601)17:1<17::aid-bdd932>3.0.co;2-f

✦ Synopsis

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90pgkg-' of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90pgkg-I are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 pg kg-I. The values of the plasma clearance (CL), steady-state volume of distribution (V,,), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376mLminP1, 140 L, 1.8 h, and 1-7 h, respectively, and remained essentially constant over the dosage range of 10-60 pg kg-I of IV MK-462. However, as the dose increased from 60 to 90pgkg-l, the mean value of the apparent CL decreased from 1376 to 807mLmin-'. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V,, value of MK-462 remained essentially constant over the dosage range of 10-90 pg kg-I of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL,) = 2028 mL min-I, and mean transit time in the peripheral tissues (MTT,) = 0.74 h. The mean values of AUC, C, , , t,,, and apparent tIl2 of MK-462 in 12 subjects each receiving a 40mg tablet of MK-462 without breakfast were 330ng.hmL-I, 77ngmL-', 1.6h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by -20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C,, and apparent tIl2 of MK-462.