Pharmacokinetic-pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration-EEG effect relationship.

The pharmacodynamics of the gamma-aminobutyric acid (GABA) uptake inhibitor (R)-N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) was quantified in rats following chronic (14 days) administration by an integrated pharmacokinetic-pharmacodynamic (PK/PD) modelling approach. The increase in beta activity (11.5-30 Hz) of the EEG as derived by fast Fourier transformation analysis was used as pharmacodynamic endpoint. Two groups of male Wistar rats were treated for 14 days with either tiagabine at a steady-state concentration of 198+/-10 ng ml(-1) or placebo. Chronic treatment with tiagabine resulted in an increase of the EEG effect parameter by 38+/-2 microV. In the PK/PD experiment the time course of the EEG effect was determined in conjunction with the decline of drug concentrations after an i.v. bolus administration of 10 mg kg(-1). The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chronic treatment on the pharmacokinetics was observed. Hysteresis between plasma concentration and EEG effect was accounted for by incorporation of an 'effect-compartment' in the model. The observed relationship between tiagabine concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the pharmacodynamic parameters were observed. The population means for the different pharmacodynamic parameters were: maximum EEG effect 82 microV, EC(50) 486 ng ml(-1), Hill factor 2.0 and k(e0) 0.060 min(-1). In the in vitro [(3)H]GABA uptake assay no changes in affinity or functionality for the GABA uptake transporter were observed, consistent with the absence of adaptation. It is concluded that chronic treatment with tiagabine in an effective dose range for 14 days does not produce functional adaptation to tiagabine-induced GABA-ergic inhibition in vivo.

Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels.

1. The objective of this investigation was to determine the influence of amygdala kindling on the pharmacodynamics of tiagabine in vivo, using quantitative EEG parameters and extracellular GABA concentrations as pharmacodynamic endpoints. In integrated pharmacokinetic/pharmacodynamic (PK/PD) studies the time course of these effects was determined in conjunction with plasma concentrations following intravenous administration of 10 mg kg(-1). An 'effect compartment' model was used to derive individual concentration - effect relationships. 2. ++Tiagabine produced an increase in the amplitude of the 11.5 - 30 Hz frequency band of the EEG. The relationship between concentration and EEG effect was non-linear and described by the Hill equation. 3. In kindled rats the EC(50) was reduced to 291 ng ml(-1) from the original value of 521 ng ml(-1) in controls. The values of all other parameters were unchanged. In kindled rats the baseline extracellular GABA concentration was increased to 1.58 microM from 0.74 microM in controls. The relationships between tiagabine concentration and extracellular GABA concentration were again non-linear and described by the Hill equation. No differences were observed between kindled rats and controls. In the synaptoneurosmal preparation in vitro no changes in the functioning of the GABA transporter were observed. 4. It is concluded that unlike the situation with midazolam, there is no resistance to the EEG effect of tiagabine in the kindling model of experimental epilepsy. The observed shift in the concentration - EEG effect relationship to lower concentrations can presumably be explained by the increase in the baseline GABA levels.

Pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam in healthy volunteers: an interethnic comparative study between Japanese and European volunteers.

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.