L-697,639, a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in vitro, was administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single and multiple oral doses. Single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, produced no clinically important adverse events. Dose proportionality with respect to AUC was seen over the range of 25-100 mg administered as a single dose. Single doses of 200 mg and 500 mg resulted in an increase in AUC and Cmax that was less than proportional to the increase in dose. The mean Cmax after single doses of 25 and 500 mg were 0.9 and 5.8 microM respectively. Mean Tmax values ranged from 1.7-3 h. Mean AUCs (0-48 h) were from 6.05 to 50.3 microM h after doses from 25 to 500 mg respectively. After the 500-mg dose less than 0.7% appeared unchanged in the urine over 48 hours. During multiple doses, steady-state was reached on day 3 and slight accumulation occurred (approximately 1.5-fold). L-697,639 was well tolerated for up to ten days at doses that resulted in mean steady-state trough concentrations that exceed their in-vitro susceptibilities.