The aim of these two studies was to evaluate the safety and pharmacokinetics of 
oral nalmefene, a new orally effective opioid antagonist. In the first study, 
single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were 
administered in double-blind fashion to four groups of healthy men. There were 
six subjects in each group; four received nalmefene and two received placebo. 
The drug was well tolerated at all dose levels with only mild and transient side 
effects, such as lightheadedness, at the higher doses. Model-independent 
pharmacokinetic analysis of the plasma concentration-time data showed that 
nalmefene was rapidly absorbed and had an elimination half-life that ranged from 
seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = 
.97) between administered dose and total area under the curve at each dose 
level. Only about 4% of the dose was excreted in the urine as unchanged 
nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase 
hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men 
were initially administered a single 50-mg dose of drug, and plasma samples were 
obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg 
q12h was then started and continued for seven days. Plasma samples were 
collected immediately before each dose and at selected times for up to 48 hours 
after the last dose. The drug was well tolerated by all subjects, and no 
clinically significant adverse effects were observed during the seven-day 
administration period.(ABSTRACT TRUNCATED AT 250 WORDS)