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 inhibito r (R)-N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) wa s quantified in rats following chronic (14 days) administration by an integ rated pharmacokinetic-pharmacodynamic (PK/PD) modelling approach. The incre ase in beta activity (11.5-30 Hz) of the EEG as derived by fast Fourier tra nsformation analysis was used as pharmacodynamic endpoint. Two groups of ma le Wistar rats were treated for 14 days with either tiagabine at a steady-s tate concentration of 198 +/- 10 ng ml(-1) or placebo. Chronic treatment wi th tiagabine resulted in an increase of the EEG effect parameter by 38 +/- 2 muV. In the PK/PD experiment the time course of the EEG effect was determ ined in conjunction with the decline of drug concentrations after an i.v. b olus administration of 10 mg kg(-1). The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chr onic treatment on the pharmacokinetics was observed. Hysteresis between pla sma concentration and EEG effect was accounted for by incorporation of an ' effect-compartment' in the model. The observed relationship between tiagabi ne concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the ph armacodynamic parameters were observed. The population means for the differ ent pharmacodynamic parameters were: maximum EEG effect 82 muV, EC50 486 ng ml(-1), Hill factor 2.0 and k(e0) 0.060 min(-1). In the in vitro [H-3]GABA uptake assay no changes in affinity or functionality for the GABA uptake t ransporter 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 CAB A-ergic inhibition in vivo. (C) 2000 Elsevier Science B.V. All rights reser ved.