**3.6.1 PK-PD model**

The GH plasma levels, can serve as a Surrogate Marker for assessing the GABAergic transmission in the CNS and is therefore a useful tool for dosage regimen calculation of the new antiepileptic drugs and for the right choice of therapeutic strategy, since, the oral administration of drugs that facilitates GABAergic transmission, among them the antiepileptics, cause a rise of growth hormone plasma levels, GH, in a dose-dependent manner, being GH release induced by gamma-aminobutyric acid, GABA, and mediated by a dopaminergic mechanism, via dopamine release at suprapituitary level (Cavagnini et al 1980a, 1980b; Powers et al 2008).

Thus, eg, Diazepam administration causes a dose-dependent rise in GH and the reached plasmatic peak is related to the plasma level of the drug. This highly significant correlation of the serum concentrations, between GH and Diazepam, has been found, also, with other AEDs, that act via the release or facilitation of GABAergic transmission, so we can use the plasma levels of GH as a Biomarker for dose adjustment of Diazepam, Topiramate, Gabapentin, Oxcarbazepine, Valproate and Levetiracetam, being the optimal dose, that which allow us to achieve the Clinical Surrogate Endpoint of GH equal to 15-25 ng/ml (Monteiro et al 1990; Monteleone et al 1987; Syvälahti & Kanto 1975).

Once the steady-state and a pharmacological response, ranging between the 20-80% of maximal effect, is reached we can estimate the optimal dose required to achieve the Clinical Surrogate Endpoint of GH equal to 15-25 ng/ml, using equation 2.
