Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of 5-HT_1AReceptor Agonists: Estimation of in Vivo Affinity and Intrinsic Efficacy on Body Temperature in Rats

Abstract

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 Ϫ1.27 for WAY-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 ; r 2 ϭ 0.55, P Ͼ 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]; r 2 ϭ 0.76, P Ͻ 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.Recently a semi-mechanistic pharmacokinetic-pharmacodynamic model for the effects of 5-HT 1A agonists on body temperature has been proposed, which is based on dynamical systems analysis. It has been demonstrated that this model can be used to estimate both the in vivo potency and the intrinsic activity of 5-HT 1A agonists. In the mean time, this model has been successfully applied to characterize the in vivo concentration-effect relationships of several 5-HT 1A agonists including R-and S-8-OH-DPAT, flesinoxan, and buspirone (Zuideveld et al., , 2002a(Zuideveld et al., , 2002b. Furthermore, the in vivo affinity of the 5-HT 1A receptor antagonist WAY-100,635 could be estimated on basis of the analysis of the competitive interaction with R-8-OH-DPAT (Zuideveld et al., 2002b).The previously proposed model is semi-mechanistic in the sense that it uses a mechanistic model for the characterization of the transduction process. Specifically, 5-HT 1A agonists cause lowering of body temperature by modulation of the set-point for maintenance of the body temperature in a direct concentration-dependent manner . Therefore a mechanism-based set-point model, which is based on dynamical systems analysis, was proposed and successfully implemented in the integrated PK-PD model to describe the complex time profile of the effects of 5-HT 1A Article, publication date, and citation information can be found at

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

“…However, flesinoxan_s EC 50 required adjustment in order to adequately predict the hypothermic and cortisol response in man. In this respect it is important to note that in a meta-analysis of various 5-HT 1A receptor agonist effects on hypothermia Zuideveld et al (17) have shown that the affinity of flesinoxan is underestimated by approximately a factor 30. This apparent inconsistency can be explained by either a large difference in receptor reserve or a disproportionate difference in flesinoxan blood and effect site concentration.…”

“…In a meta-analysis of various 5-HT 1A receptor agonist effects on hypothermia, Zuideveld et al (17) have shown that the affinity of flesinoxan is underestimated by approximately a factor 30. The underestimation is likely to be due to the fact that flesinoxan is subject to an active transport mechanism, resulting in a drug receptor association rate constant (Ka), estimate based on blood concentrations which may not be representative of the concentration at the site of the 5-HT 1A receptor (18).…”

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine and Fentanyl in Rats: Role of Receptor Equilibration Kinetics

“…In recent years, there has been an increasing interest in the application of receptor theory in PK/PD modeling with the aim to predict in vivo concentration-effect relationships (Van der Graaf and Danhof, 1997). An important feature of these mechanism-based models is the strict distinction between drug-and system-related properties ( Van der Graaf et al, 1999;Visser et al, 2002;Zuideveld et al, 2004). A common feature of these models is that rapid equilibration of the drug-receptor complex is assumed.…”

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory-Depressant Effect of Buprenorphine and Fentanyl in Rats

“…The incorporation of principles from receptor theory has been a key element in this development (Van der Graaf and Danhof, 1997). A specific feature of mechanism-based PK/PD models is the separation between a drug-specific part, characterizing the interaction of the drug with the biological system in terms of in vivo affinity and intrinsic efficacy, and a biological system-specific part characterizing the in vivo stimulus-response relationship (Visser et al, 2002;Zuideveld et al, 2004;Jonker et al, 2005). Typically the interaction of the drug with the biological system is described by a hyperbolic function.…”