Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

Abstract

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.

Electroencephalogram-based pharmacodynamic measures: a review

“…An example of such a study is the work by Jonker et al [118] to assess the pharmacodynamic interaction between midazolam (an allosteric modulator for the GABA A -type receptor) and the anticonvulsant tiagabine (which inhibits the uptake of GABA at the synapse). The experiments demonstrated that midazolam and tiagabine express an additive in-vivo pharmacodynamic interaction, rather than synergistic.…”

“…In order for this approach to succeed, such a model should be backed by substantial supportive evidence. For example, both the BZD drug class [112,113,114,115,116,117,118] and opioid drug class [104,105,106,107,108] have demonstrated a consistent EEG-concentration relationship that is well-characterized by pharmacodynamic models. The benefits of such a robust EEG-based pharmacodynamic model for drug development can include expediting clinical trials, enhanced clinical trial safety, reduction in clinical trial cost, or a combination of the three.…”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…However, incorporating drug-target binding into the model might explain the same delay and could be more mechanistic [64]. On the other hand, when solving the shortcomings in knowledge on target site distribution of drugs, the principles of the operational model of agonism (receptor theory) will provide the basis for future developments in drug development by classifying drugs and predicting their mechanism of action in pharmacology [65][66][67][68]. PK-PD approaches have typically focused on anticipated drug effects.…”

“…Currently, to link (neuro-)PK to the systems response, PK-PD modeling is often applied. These models can include target activation (receptor theory [65][66][67][68]), signal transduction [57][58][59][60][61], interspecies differences [62], tolerance and sensitization [63], and intra-and interindividual variability. Also here, it should be noted that parameter values of PK, PD, and disease processes should not be obtained in isolation, and in different systems, because in such manner interrelationships and systems dependencies of processes cannot be assessed.…”

Biomarkers and Therapeutic Drug Monitoring in Psychiatry

“…Inhibition of the enzyme GSK-3B, whose complete mechanism in relation with BD has not yet been hypothesized (Jonker et al 2003). 2.…”