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

Abstract

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 GABA A receptor modulators. The EEG effects of nine prototypical GABA A receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one ␤-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 (EC 50 ) 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 (K PD ) and the in vivo intrinsic efficacy (e PD ). The values of K PD ranged from 0.41 Ϯ 0 ng⅐ml Ϫ1 for bretazenil to 436 Ϯ 72 ng⅐ml Ϫ1 for clobazam and the values for e PD from Ϫ0.27 Ϯ 0 for methyl 6,7-dimethoxy-4-ethyl-␤-carboline-3-carboxylate to 0.54 Ϯ 0.02 for diazepam. Significant linear correlations were observed between K PD for unbound concentrations and the affinity in an in vitro receptor bioassay (r ϭ 0.93) and between e PD and the GABA-shift in vitro (r ϭ 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABA A receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABA A receptor modulators behave as partial agonists relative to neuroactive steroids.The pharmacokinetic-pharmacodynamic correlations of benzodiazepines have been the subject of numerous studies in both animals and humans for review, see Laurijssens and Greenblatt, 1996), but the predictive value of the proposed models seems to be limited. To date, there is an increasing interest in the development of mechanism-based PK/PD models because they allow the prediction of drug effects in vivo in a strict, quantitative manner on the basis of results obtained in in vitro test systems. These models not only provide a scientific basis for the prediction of drug effects in humans on the basis of results obtained in animal studies but also allow a mechanistic understanding for observed interindividual variability in drug response (Van der Graaf and Danhof, 1997).The need for mechanism-based modeling is illustrated by the difficulty of predicting the in vivo intrinsic activity of benzodiazepine receptor partial agonists in humans on the basis of results obtained in preclinical investigations. For example, in humans, the new benzodiazepine Ro 46-2153 behaved as a full agonist, whereas it was selected from preclinical studies based on its partial agonist properties (Goggin et al., 2000).In mechanism-based PK/PD models that are based on receptor theory, a separation is made between th...

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

“…Similar correlations have been reported for calcium channel antagonists using a receptor association/dissociation model (Shimada et al, 1996) and also for A 1 adenosine receptor agonists and GABA A receptor modulators using a different mechanism-based PK/PD model based on receptor theory (Van der Graaf et al, 1999;Visser et al, 2003). Moreover, the ability to estimate an in vivo K D allows a strict quantitative comparison with the antinociceptive effect of other compounds.…”

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

“…These values of system-specific parameters can only be estimated by in vivo analysis [14] . In contrast, drugspecific parameters (ie, E max and EC 50 ) can often be predicted based on in vitro bioassays [43,44] . As a result, this mechanismbased PK/PD approach may serve as a tool for predicting the extent of CYP3A1/2 induction by potential inducers and the magnitude of changes in the PK of a probe substrate, based on drug-specific parameters and the PK of the inducers.…”

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

“…Hence, the decreased efficacy of GABAergic drugs observed in epilepsy is most likely caused by a lower number of GABA A receptors rather than an alteration in binding affinity (K D ) to the receptors. (27), and 54.5 ngÁmL 21 in rat brain homogenates (28). The K D estimate, 5.9 6 0.9 ngÁmL 21 , obtained in the present study is also in line with previously published studies (17,18,(25)(26)(27)(28).…”

“…(27), and 54.5 ngÁmL 21 in rat brain homogenates (28). The K D estimate, 5.9 6 0.9 ngÁmL 21 , obtained in the present study is also in line with previously published studies (17,18,(25)(26)(27)(28). On the basis of time-activity data obtained in a previous study when 11 C-flumazenil was administered without the addition of unlabeled flumazenil (18), the doses used in the present study resulted in approximate occupancy levels of 30%-40% for 4-mg, 60%-70% for 20-mg, 70%-80% for 100-mg, and around 90% for 400-mg dose groups.…”