Objective  To investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of buagafuran after single, and twice-daily repeated oral doses of 60 or 120 mg.

  Methods  In this double-blind, randomized, placebo-controlled, parallel study, 7 male and 7 female healthy subjects were enrolled in each dosing cohort and were administered with buagafuran or placebo based on a 5:2 randomized allocation schedule. Subjects took a single oral dose of buagafuran or placebo on the first day. After 48 hours, subjects started to receive twice daily repeated administration for 4.5 days. Within the 48 hours following the first and the last study doses, the serial blood and urine samples were collected for PK assays. Meanwhile, PD measurements were performed, which included body sway, choice reaction time, digit span task, visual analogue scale (VAS) of Bond and Lader, and VAS of Bowdle.

  Results  After the single oral dose of buagafuran, the mean PK parameters were: C_max, (37.7±18.4) ng/ml and (95.8±34.8) ng/ml; area under the plasma concentration-time curve (AUC)_0-t, (108±46) h·ng/ml and (336±104) h·ng/ml; apparent clearance, (581±203) L/h and (367±122) L/h; t_1/2, (10.4±7.1) hours and (19.8±6.5) hours for 60 and 120 mg buagafuran, respectively. With twice daily repeated administration for 4.5 days, the mean C_max were (48.5±32.2) ng/ml and (118.0±20.3) ng/ml, with a mean AUC_0-t of (241±122) h·ng/ml and (656±135) h·ng/ml for 60 and 120 mg, respectively. No PD parameters showed clinically or statistically significant difference between these two dosing schemes except for VAS alertness, VAS external feeling, and VAS internal feeling.

  Conclusions  The plasma exposure of buagafuran attains a steady state with approximately 2-3 times of accumulation after twice-daily repeated dosing for 24 hours. The oral administrations with 60 or 120 mg buagafuran were safe and well tolerated in the healthy subjects. The absence of PD findings may be attributed to the insufficient validation of the PD measurements.