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NEUROPHARMACOLOGY

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1A Receptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands (K.P.Z., M.D.); Pfizer Global Research and Development, Discovery Biology, Sandwich, Kent, United Kingdom (P.H.V., D.N., R.T., N.P.); F. Hoffmann-La Roche, Modeling and Simulation and Biometrics Groups, Basel, Switzerland (K.P.Z., P.J.); and Mathematical Institute, Leiden University, Leiden, The Netherlands (L.A.P.)

The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT_1A agonists were analyzed on the basis of a recently proposed semi-mechanistic PK-PD model for the effect on body temperature. The resulting concentration-effect relationships were subsequently analyzed on the basis of the operational model of agonism to estimate the operational affinity (pK_A) and efficacy (log ) at the 5-HT_1A receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pK_i) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT_1A agonists wide differences in in vivo affinity and efficacy were observed, with values of the pK_A ranging from 5.67 for flesinoxan to 8.63 for WAY-100,635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] and of the log ranging from –1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)--phenyl-1-piperazine-propanamide] to 0.62 for R-(+)-8-hydroxy-2-[di-n-propylamino)tetralin. Poor correlations were observed between the in vivo receptor affinity (pK_A) and the affinity estimates in the in vitro receptor binding assay (pK_i; r² = 0.55, P > 0.05), which could in part be explained by differences in blood-brain distribution. In contrast, a highly significant correlation was observed between the efficacy parameters in vivo (log ) and in vitro (log [agonist ratio]; r² = 0.76, P < 0.05). Thus by combining the previously proposed semi-mechanistic PK-PD model for the effect on body temperature with the operational model of agonism, a full mechanistic PK-PD model for 5-HT_1A receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy.

Address correspondence to: Prof. Meindert Danhof, Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. E-mail: M.Danhof{at}LACDR.LeidenUniv.nl

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