Population Pharmacokinetic/Pharmacodynamic Analysis of Different Subunit Selective GABAergic Ligands in an Animal Model of Epilepsy

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Objectives: Changes in GABA_A-receptor functionality play an important role in many forms of epilepsy. One of the causes of these changes may be alteration in subunit composition of the receptor. In the present study the functionality of the GABA_A-receptor was studied in vivo in the post Status Epilepticus (post-SE) rat model, in which the SE was induced by ip injections of kainic acid (KA). Different subunit selective GABAergic ligands were used: midazolam (MDZ, selective for gamma₂), alphaxalone (ALP, selective for delta), and zolpidem (ZPD, selective for alpha₁).

Methods: A PK/PD experiment with a GABAergic ligand (MDZ, n=8, ALP, n=6, ZPD, n=4) was performed in male Sprague Dawley rats before and at 4 or 14 days after induction of SE. The power of β-frequency of the cortical EEG was used as a measure for the effect. The results were analysed using the mechanism based PK/PD model reported by Visser et al (JPET, 2002;302:1158-1167), comprising a separate characterization of the receptor activation process and the stimulus-response relationship. A single and unique stimulus-response relationship was assumed for all ligands. If only changes in subunit composition underly changes in functionality of the GABA_A-receptor in epileptic animals, this will be exclusively reflected in alterations in the in vivo intrinsic efficacy (e_PD).

Results: Analysis of the data resulted in a significant decrease in effect of MDZ and ZPD after induction of SE (e_PD = 39% or 87% of control respectively), whereas the effect of ALP was significantly increased (e_PD up to 129%). This is indeed in favour of an alteration in subunit composition, specifically an exchange of gamma-subunits to delta-subunits. Furthermore, the data indicate that the transducer function is altered as well by epilepsy. Further refinements of the model to characterize and explain these alterations are currently under investigation.

Conclusions: Using a mechanism based PK/PD model, subunit-selective alterations in epilepsy, expressed in changes in e_PD are shown. Moreover, as the model is able to distinguish between the receptor activation process and the stimulus-response relationship, analysis of alterations in the transducer function will provide deeper insight in the process of epileptogenesis.