PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg^?1of 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 90 μg kg^?1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg^?1. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min^?1, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg^?1 of IV MK-462. However, as the dose increased from 60 to 90 μg kg^?1, the mean value of the apparent CL decreased from 1376 to 807 mL min^?1. 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_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg^?1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min^?1, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL^?1, 77 ng mL^?1, 1·6 h, 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_max and apparent t_½ of MK-462.