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Vol. 304, Issue 1, 88-101, January 2003

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of the Electroencephalogram Effects of GABAA Receptor Modulators: In Vitro-in Vivo Correlations

S.A.G. Visser1 , F.L.C. Wolters, J. M. Gubbens-Stibbe, E. Tukker, P. H. van der Graaf, L. A. Peletier and M. Danhof

Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands (S.A.G.V., F.L.C.W., J.M.G.-S., E.T., M.D.); Pfizer Global Research and Development, Discovery Biology, Sandwich, Kent, United Kingdom (P.H.v.G.); and Mathematical Institute, Leiden University, Leiden, The Netherlands (L.A.P.)

A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model for neuroactive steroids, comprising a separate characterization of 1) the receptor activation process and 2) the stimulus-response relationship, was applied to various nonsteroidal GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta -carboline) were determined in rats in conjunction with plasma concentrations. Population PK/PD modeling revealed monophasic concentration-EEG effect relationships with large differences in potency (EC50) and intrinsic activity between the compounds. The data were analyzed on the basis of the mechanism-based PK/PD model for (synthetic) neuroactive steroids on the assumption of a single and unique stimulus-response relationship. The model converged yielding estimates of both the apparent in vivo receptor affinity (KPD) and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 ± 0 ng·ml-1 for bretazenil to 436 ± 72 ng·ml-1 for clobazam and the values for ePD from -0.27 ± 0 for methyl 6,7-dimethoxy-4-ethyl-beta -carboline-3-carboxylate to 0.54 ± 0.02 for diazepam. Significant linear correlations were observed between KPD for unbound concentrations and the affinity in an in vitro receptor bioassay (r = 0.93) and between ePD and the GABA-shift in vitro (r = 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists relative to neuroactive steroids.

1 Current address: AstraZeneca R&D Södertälje, DMPK and BAC, S 15185 Södertälje, Sweden.

0022-3565/03/3041-0088$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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