Summary:Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ␥-aminobutyric acid subtype A (GABA A ) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake.Methods: The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5-to 30-Hz frequency band was used as the pharmacodynamic end point.Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-E max model. The pharmacodynamic parameter estimates of TGB were: E max ‫ס‬ 327 ± 10 V, EC 50 ‫ס‬ 392 ± 20 ng/ml, and n H ‫ס‬ 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism.Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.