Vol. 291, Issue 2, 547-554, November 1999

Pharmacokinetic-Pharmacodynamic Modeling of Tolerance to the Prolactin-Secreting Effect of Chlorprothixene after Different Modes of Drug Administration¹

Metin Bagli, Richard Süverkrüp, Ralph Quadflieg, Gereon Höflich, Siegfried Kasper¹ , Hans-Jürgen Möller² , Michael Langer, Uwe Barlage and Marie Luise Rao

From the Department of Psychiatry and Psychotherapy (M.B., G.H., S.K., H.-J.M., M.L.R.) and Institute for Pharmaceutical Technology (R.S., R.Q.), University of Bonn, Bonn, Germany; and Bayer Vital GmbH, Leverkusen, Germany (M.L., U.B.)

The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A three-compartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject's sensitivity to drugs and the time course of adaptation.