Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

ABSTRACT

BACKGROUND AND OBJECTIVES: As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. METHODS: In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. RESULTS: Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28 ± 18.99, 230.76 ± 29.16 and 352.67 ± 42.94 µg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09 ± 59.66, 524.50  ± 72.87 and 822.68 ± 95.21 µg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72 ± 61.65, 536.06 ± 78.13 and 832.07 ± 96.91 µg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05 ± 0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. CONCLUSIONS: S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.