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Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double‐blind, placebo‐controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age‐ and sex‐matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 ± 0.165 mL/min/kg and 1.17 ± 0.492 mL/min/kg, and half‐life (t1/2) was 22.1 ± 4.96 hours and 21.5 ± 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time‐effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration‐effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs. Such studies can form a rational basis for comparative clinical trials.

Objective: To study the pharmacodynamic effects of intravenous temazepam after different infusion rates to pseudo steady-state concentrations.Methods: This was a randomized, double-blind, placebo-controlled crossover study in an academic department of clinical pharmacology. Subjects were nine healthy volunteers. A computerized infusion pump was used to obtain target plasma concentrations of temazepam after 30 or 120 minutes and to maintain these levels for 2 hours. A vehicle inftision, similar to the 30-minute (fast) infusion was used as a placebo control. Infusion schedules were based on data obtained from individual subjects after inftision of 0.4 mg/kg temazepam in 30 minutes. Target plasma concentrations were chosen to induce subhypnotic effects and averaged ( ± SD) 597 ± 123 ng/ml. Venous plasma concentrations of temazepam were measured by HPLC. Free fractions of temazepam were assessed at the start of the pseudo steady-state concentration intervals. Electroencephalogram alpha and beta amplitudes, saccadic peak velocity, and saccadic latency were used as pharmacodynamic parameters.Results: The rate of change of plasma concentrations averaged 21 ± 4 ng/ml · min-1during fast infusion and 5 ± 1 ng/ml · min-1during slow infusion of temazepam. Average pseudo steady-state concentrations were 639 ± 132 ng/ml after fast infusion and 629 ± 133 ng/ml after slow infusion. At the onset of pseudo steady-state concentration intervals the average free fractions of temazepam were 44% (95% confidence interval, 19% to 61%) lower for slow than for fast infusions. Compared with the slow infusion, electroencephalogram beta amplitudes were significantly larger during the first 30 minutes of pseudo steady-state concentration after fast infusion of temazepam. No significant differences were found for the other parameters. There was a slight decline of temazepam effects during the pseudo steady-state concentration intervals for all parameters after the fast infusion and for saccadic peak velocity and saccadic latency after the slow infusion.Conclusions: The pharmacodynamic effects of intravenous temazepam may depend partly on the rate of administration. Differences in pharmacodynamic effects after fast and slow infusions could be caused by changes in protein binding over time.Clinical Pharmacology and Therapeutics (1994) 55, 535–545; doi:10.1038/clpt.1994.67