Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Abstract

The neuroactive steroid alphaxalone reveals a complex biphasic concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The proposed model is based on receptor theory and aims to separate the drug-receptor interaction from the transduction of the initial stimulus into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered intravenously in various dosages. The pharmacokinetics were described by a two-compartment model, and parameter estimates for clearance, intercompartmental clearance, volume of distribution 1 and 2 were 158 Ϯ 29 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 143 Ϯ 31 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 122 Ϯ 20 ml ⅐ kg Ϫ1 and 606 Ϯ 48 ml ⅐ kg Ϫ1 , respectively. Concentration-effect relationships exhibited a biphasic pattern and delay in onset of effect. The hysteresis was described on the basis of an effect-compartment model with C max as covariate. The pharmacodynamic model consisted of a receptor model, featuring a monophasic saturable receptor activation model in combination with a biphasic stimulus-response model. The in vivo affinity (K PD ) was estimated at 432 Ϯ 26 ng ⅐ ml Ϫ1 . Unique parameter estimates were obtained that were independent of the dose and the duration of the infusion. In conclusion, we have shown that this mechanism-based approach, which separates drug-and system-related properties in vivo, was successfully applied for the characterization of the biphasic effect versus time patterns of alphaxalone. The model should be of use in the characterization of other biphasic responses.The sedative-hypnotic and anesthetic properties of a wide range of natural and synthetic steroids were first shown by Selye (1942). This initial work led to the introduction of the synthetic neuroactive steroid alphaxalone (5␣-pregnan-3␣-ol-11,20-dione) into clinical medicine (Sear, 1996). Alphaxalone exerts its selective action via a specific binding site at the GABA A receptor complex and does not interact with any of the classical cytosolic hormonal steroid receptors (Paul and Purdy, 1992;Lambert et al., 1995). Detailed mechanistic investigations have revealed a dual mechanism of action for alphaxalone. Low concentrations of alphaxalone allosterically modulate the amplitude of GABA-induced ion currents, whereas alphaxalone at higher concentrations (Ն1 M) acts as an agonist, similar to that observed by barbiturates (Cottrell et al., 1987;Paul and Purdy, 1992;Lambert et al., 1995). Recently, there has been a renewed interest in neuroactive steroids in relation to the development of novel strategies for the treatment of anxiety, insomnia, migraine, depression, and seizure disorders (Gasior et al., 1999). However, very few attempts have been made to study neuroactive steroids in vivo on the basi...

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

“…Mechanism-based PK/PD models provide a unique basis to characterize the effects of drugs in terms of in vivo potency and intrinsic activity (E max ). In recent years, this approach has been successfully applied to explore the concentrationeffect relationships of several compounds belonging to different drug classes (Van der Graaf et al, 1999;Visser et al, 2002). In the present investigation, maximal antinociceptive effect could not be estimated from the concentration-effect relationships.…”

“…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.…”

Learning curve of vessel cannulation in rats using cumulative sum analysis

“…routes; the first for infusing the drug and the second for blood sampling [23,24]. In this study we evaluated the learning curve for cannulating the femoral and the external jugular vein, two of the most commonly used i.v.…”

Towards a Dynamic Neuropharmacology: Integrating Network and Receptor Levels

“…A theoretical framework with intermediate complexity based on pharmacokineticspharmacodynamics (PK/PD) was suggested to model the effects of GABA modulators on EEG in a series of papers [32,33]. Pharmacokinetics generally is supposed to describe drug disposition and biophase equilibration, diffusion included.…”