concentration-EEG Effect Relationship Research Articles

Effect of 7-day exposure to midazolam on electroencephalogram pharmacodynamics in rats: a model to study multiple pharmacokinetic-pharmacodynamic relationships in individual animals.

The objective of this study was to determine the concentration-electroencephalogram (EEG) relationships for midazolam, a full-agonist benzodiazepine ligand, on multiple occasions in individual rats, and to examine the effect of chronic midazolam exposure on that relationship. Rats were chronically instrumented with venous and arterial cannulas, and cortical EEG electrodes. The rats received either: 7 days of midazolam 10 mg kg(-1) intravenously once a day (midazolam group); or midazolam on days 1 and 7 and vehicle on days 2-6 (vehicle group). Concentration-effect relationships were determined on days 1, 4 and 7 from multiple blood and EEG samples before and after the administration of the midazolam dose. The concentration-EEG effect relationships were consistent with a sigmoidal Emax (maximal effect) model. No differences in pharmacokinetic or pharmacodynamic parameters were found between day 1 and day 7 in either group. However, in the midazolam group, both the fraction unbound of midazolam in serum and the EC50 (concentration at half-maximal effect) for free midazolam increased from days 1-7 by 35 +/- 3% and 54 +/- 25%, respectively (means +/- s.d., P< 0.05). This may be related to decreased serum albumin levels in the midazolam group (-19+5%, P < 0.05) which, in turn, could be explained by the sedation associated with daily midazolam treatment. We concluded that concentration-EEG effect relationships can be studied on multiple occasions in individual animals, reducing animal use and variability. A modest degree of tolerance to midazolam was found with this paradigm, the effect only being evident after correction for the fraction unbound of midazolam.

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro-in vivo correlations.

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 GABAA receptor modulators. The EEG effects of nine prototypical GABAA receptor modulators (six benzodiazepines, one imidazopyridine, one cyclopyrrolone, and one beta-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 (EC50) 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 (KPD) and the in vivo intrinsic efficacy (ePD). The values of KPD ranged from 0.41 +/- 0 ng.ml(-1) for bretazenil to 436 +/- 72 ng.ml(-1) for clobazam and the values for e(PD) from -0.27 +/- 0 for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate to 0.54 +/- 0.02 for diazepam. Significant linear correlations were observed between KPD for unbound concentrations and the affinity in an in vitro receptor bioassay (r = 0.93) and between e(PD) and the GABA-shift in vitro (r = 0.95). The findings of this investigation show that the in vivo effects of nonsteroidal GABAA receptor modulators and (synthetic) neuroactive steroids can be described on the basis of a single unique transducer function. In this paradigm, the nonsteroidal GABAA receptor modulators behave as partial agonists relative to neuroactive steroids.

In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat.

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta-frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC(50)), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar K(i) values. At a total serum ketoconazole of 2 microg/ml (3.76 microM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine.

Pharmacokinetic–pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration–EEG effect relationship

The pharmacodynamics of the γ-aminobutyric acid (GABA) uptake inhibitor ( R)- N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) was quantified in rats following chronic (14 days) administration by an integrated pharmacokinetic–pharmacodynamic (PK/PD) modelling approach. The increase in β activity (11.5–30 Hz) of the EEG as derived by fast Fourier transformation analysis was used as pharmacodynamic endpoint. Two groups of male Wistar rats were treated for 14 days with either tiagabine at a steady-state concentration of 198±10 ng ml −1 or placebo. Chronic treatment with tiagabine resulted in an increase of the EEG effect parameter by 38±2 μV. In the PK/PD experiment the time course of the EEG effect was determined in conjunction with the decline of drug concentrations after an i.v. bolus administration of 10 mg kg −1. The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chronic treatment on the pharmacokinetics was observed. Hysteresis between plasma concentration and EEG effect was accounted for by incorporation of an ‘effect-compartment’ in the model. The observed relationship between tiagabine concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the pharmacodynamic parameters were observed. The population means for the different pharmacodynamic parameters were: maximum EEG effect 82 μV, EC 50 486 ng ml −1, Hill factor 2.0 and k e0 0.060 min −1. In the in vitro [ 3H]GABA uptake assay no changes in affinity or functionality for the GABA uptake transporter were observed, consistent with the absence of adaptation. It is concluded that chronic treatment with tiagabine in an effective dose range for 14 days does not produce functional adaptation to tiagabine-induced GABA-ergic inhibition in vivo.

Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.

A mechanism-based model is applied to analyse adaptive changes in the pharmacodynamics of benzodiazepines upon chronic treatment in rats. The pharmacodynamics of midazolam was studied in rats which received a constant rate infusion of the drug for 14 days, resulting in a steady-state concentration of 102 +/- 8 ng x ml(-1). Vehicle treated rats were used as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. The relationship between midazolam concentration and EEG effect was non-linear. In midazolam pre-treated rats the maximum EEG effect was reduced by 51 +/- 23 microV from the original value of 109 +/-15 microV in vehicle treated group. Analysis of this change on basis of the operational model of agonism showed that it can be explained by a change in the parameter tissue maximum (Em) rather than efficacy (tau). In the in vitro studies no changes in density, affinity or functionality of the benzodiazepine receptor were observed. It is concluded that the observed changes in the concentration-EEG effect relationship of midazolam upon chronic treatment are unrelated to changes in benzodiazepine receptor function.

Pharmacokinetic-pharmacodynamic analysis of the EEG effect of alfentanil in rats following beta-funaltrexamine-induced mu-opioid receptor "knockdown" in vivo.

The objective of this investigation was to determine the influence of pre-treatment with the irreversible mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) on the pharmacokinetic-pharmacodynamic (PK/PD) relationship of alfentanil in rats. The PK/PD correlation of alfentanil (2 mg x kg(-1) intravenously in 20 min) was determined in chronically instrumented rats using amplitudes in the 0.5-4.5 Hz frequency band of the EEG as pharmacodynamic endpoint. Beta-FNA was administered intravenously (10 mg x kg(-1)) either 35 min or 24 h prior to the PK/PD experiments. Pre-treatment with beta-FNA had no influence on the pharmacokinetics of alfentanil. The in vivo concentration-EEG effect relationships, however, were steeper and shifted towards higher concentrations with no difference between the 35-min and the 24-h pre-treatment groups. Analysis of the data on basis of the operational model agonism revealed that the observed changes could be explained by a 70-80% reduction in alfentanil efficacy in beta-FNA pre-treated rats. This is consistent with results from an in vitro receptor bioassay showing a 40-60% reduction in the number of specific mu-opioid binding sites in the brain. This investigation confirms the validity of a previously postulated mechanism-based PK/PD model for the effect of synthetic opiates in rats.

Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats: assessment of rapid functional adaptation.

1. The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological effect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic endpoint. Three groups of 6-7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14, or 4.24 mg/kg(-1) of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuously recorded and frequent arterial blood samples were collected for determination of the alfentanil concentration by gas chromatography. 2. The pharmacokinetics of alfentanil were most adequately described by a bi-exponential function. The values (mean+/-s.e., n=20) of clearance, volume of distribution at steady-state and terminal half-life were 45+/-3 ml x min(-1) x kg(-1), 0.91+/-0.09 l/kg(-1) and 23+/-1 min, respectively, and independent of the administered dose. 3. Increase in power in the 0.5-4.5 Hz (delta) frequency band of the EEG was used as the measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG effect relationships of alfentanil were derived which were successfully quantified by the sigmoidal Emax pharmacodynamic model. When the results of the first of the two consecutive infusions were compared, no systematic differences in the pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+/-s.e., n=20): E0=56+/-3 microV, Emax=93+/-8 microV, EC50=235+/-27 ng x ml(-1) and Hill factor=1.6+/-0.1, respectively. For the second of the two consecutive infusions a significantly higher value of the EC50 of 404+/-56 ng x ml(-1) was observed (P < 0.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration effect relationship can be explained by a 40% loss of functional mu-opioid receptors. 4. The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG effect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats

The purpose of the present investigation was to develop a methodology for quantification of the concentration-pharmacological effect relationship of alfentanil in individual rats by using effect parameters derived from quantitative EEG analysis. In particular, the role of the opioid-induced side effects of proconvulsant activity, hypothermia, and respiratory depression was investigated. Amplitudes in the 0.5- to 4.5-Hz frequency band of the EEG power spectrum were used as a descriptor of the effect. The pharmacokinetics and pharmacodynamics of alfentanil were determined after intravenous administration of 2000 μg/kg during 20 min. The administration of alfentanil induced paroxysmal seizure patterns in the EEG which made meaningful analysis of the EEG effect impossible. A constant infusion of midazolam (5.5 mg/kg/hr) prevented alfentanil-induced seizures. When no precautions were taken to control body temperature, analysis of the concentration-EEG effect relationship was complicated by proteresis due to alfentanil-induced hypothermia. This proteresis disappeared when body temperature was stabilized at 37.5°–38.5°C with isothermal pads. Alfentanil-induced respiratory depression was managed successfully by artificial ventilation. Adequateness of artificial ventilation was ascertained by monitoring of arterial pO 2, pCO 2, and pH. When these opioid side effects were controlled, the pharmacokinetics were most adequately described by a biexponential function. The values of the pharmacokinetic parameters were (mean ± SE, n = 7): clearance = 53 ± 6 ml.min/kg, volume of distribution = 1.19 ± 0.19 l/kg and terminal half-life = 24.5 ± 2.3 min. By pharmacokinetic-pharmacodynamic modelling, the individual concentration-effect relationships of alfentanil were derived, which were successfully characterized by the sigmoidal E max pharmacodynamic model. The values of the pharmacodynamic parameters were (mean ± SE, n = 7): E 0 = 57 ± 4 μV, E max = 95 ± 17 μV, EC 50 = 202 ± 55 ng/ml and Hill factor = 1.53 ± 0.20. No delay was observed between alfentanil concentration and effect. The results of the present study show that when side effects are controlled adequately, the concentration-EEG effect relationship of alfentanil can be characterized in individual rats using amplitudes in the 0.5- to 4.5-Hz frequency band of the EEG as a measure of the pharmacological response. The described methodology can be very useful for detailed studies into the pharmacodynamics of (new) synthetic opioids in vivo.

Thiopental uncouples hippocampal and cortical synchronized electroencephalographic activity.

Thiopental produces a concentration-dependent continuum of effects on the cortical electroencephalogram (EEG) that has been linked to behavioral measures of anesthetic depth. The complexity of the response, however, limits a clear insight into the neurophysiologic actions of thiopental. The current study investigated thiopental actions on cortical EEG and hippocampal electrical activity, to determine whether similar effects occur on both structures and to compare synchronized activity between these structures. Thiopental was administered intravenously via an implanted catheter in freely moving rats. Arterial blood oxygen/carbon dioxide concentration, thiopental concentrations, and temperature were monitored and controlled. Neocortical EEG was recorded from implanted dural surface electrodes and hippocampal neuron electrical activity was recorded from stereotaxically placed microelectrodes. Pharmacokinetic models were used to determine effect site concentrations. Thiopental produced an increase in EEG frequency and amplitude at low concentrations (15-20 micrograms/ml total plasma, approximately 10 microM unbound), which produced a loss of righting reflex. This was followed by a frequency decrease and burst suppression activity at higher concentrations (50-80 micrograms/ml, approximately 60 microM), which produced a loss of tail pinch and corneal reflexes. Higher concentrations of thiopental ( > 60 micrograms/ml) uncoupled synchronized burst discharges recorded in hippocampus and cortex. Isoelectric EEG activity was associated with concentrations of 70-90 micrograms/ml (approximately 80 microM) and a deep level of anesthesia; motor reflexes were abolished, although cardiovascular reflexes remained. In all frequency bands, similar concentration-EEG effect relationships were observed for cortical and hippocampal signals, only differing in the magnitude of response. A reversed progression of effects was observed on recovery. The results confirm earlier findings in humans and animals and demonstrate that both the hippocampus and neocortex exhibit burst suppression and isoelectric activity during thiopental anesthesia. Thiopental-induced synchronized burst activity was depressed by progressively higher concentrations. The lost synchronization suggests a depression of synaptic coupling between cortical structures contributes to anesthesia.

Pharmacodynamic interaction between midazolam and a low dose of ethanol in vivo

The pharmacokinetic and pharmacodynamic interactions between midazolam and ethanol were studied in the rat in vivo. Ethanol was given as a constant rate intravenous infusion (1.85 mg/min). The pharmacokinetics and pharmacodynamics of midazolam were determined following an intravenous dose of 5 mg/kg in 15 minutes. Amplitudes in the 11.5–30 Hz (beta) frequency band of the EEG was used as a measure of the pharmacological effect. Ethanol infusion resulted in a constant plasma alcohol concentration of 0.44 ± 0.04 g/1 (Mean ± SE) and had no effect on the baseline value of the EEG effect parameter. Also the pharmacokinetics of midazolam were unchanged. However, a significant parallel shift of the midazolam concentration-EEG effect relationship to lower concentrations was observed. These findings show that there is a pharmacodynamic interaction between midazolam and ethanol in vivo.

Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs.

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs. An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring. Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the beta frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central gamma-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.

Thiopental pharmacodynamics. I. Defining the pseudo-steady-state serum concentration-EEG effect relationship.

To assess depth of anesthesia for intravenous anesthetics using clinical stimuli and observed responses, it is necessary to achieve constant serum concentrations of drug that result in constant biophase or central nervous system concentrations. The goal of this investigation was to use a computer-controlled infusion pump (CCIP) to obtain constant serum thiopental concentrations and use the electroencephalogram (EEG) as a measure of thiopental's central nervous system drug effect. The number of waves per second obtained from aperiodic waveform analysis was used as the EEG measure. A CCIP was used in six male volunteers to attain rapidly and then maintain for 6-min time periods the following pseudo-steady-state constant serum thiopental target concentrations: 10, 20, 30, and 40 micrograms/ml. The median performance error (bias) of the CCIP using 149 measurements of thiopental serum concentrations in six subjects was +5%, and the median absolute performance error (accuracy) was 16%. Following the step change in serum thiopental concentration, the EEG number of waves per second stabilized within 2-3 min and the remained constant until the target serum thiopental concentration was changed. When the constant serum thiopental concentration was plotted against the number of waves per second for each subject, a biphasic serum concentration versus EEG effect relationship was seen. This biphasic concentration:response relationship was characterized with a nonparametric pharmacodynamic model. The awake, baseline EEG was 10.6 waves/s; at peak activation the EEG was 19.1 waves/s and occurred at a serum thiopental concentration of 13.3 micrograms/ml. At a serum thiopental concentration of 31.2 micrograms/ml the EEG had slowed to 10.6 waves/s (back to baseline) and at 41.2 micrograms/ml was 50% below the baseline, awake value. Zero waves per second occurred at serum thiopental concentrations greater than 50 micrograms/ml. Using a CCIP it is possible to establish constant serum thiopental concentration rapidly and characterize the concentration versus EEG drug effect relationship.

Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions

The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function phi(t), which is approximated by a sum of exponentials. Six male Wistar-derived rats received an iv infusion of amobarbital at a rate of 10 mg/kg per min until isoelectric periods of 5 sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5-30 Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 +/- 10%) in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concentration-EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6 +/- 1.3 mg/L. At 80.2 +/- 2.0 mg/L the EEG effect was reduced 50% below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistar-derived rats received an iv infusion of amobarbital, 10 mg per min for 15 min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50% equilibrium the effect site requires 2.5 +/- 0.3 min and the CSF 3.5 +/- 0.2 min, to reach 95% the values were, respectively, 90 +/- 27 and 15 +/- 1 min. This suggests that CSF is kinetically distinguishable from the effect site.

A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat

The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (means s and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC50. Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.

Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration.

1. The purpose of the present investigation was to quantify the concentration-pharmacological effect relationship of midazolam in individual rats by use of effect parameters derived from aperiodic EEG analysis. By varying the rate and route of administration the role of (inter)active metabolites and development of acute tolerance was evaluated. 2. The pharmacokinetics and pharmacodynamics of midazolam were determined after intravenous administration of 10 mg kg-1 during 5, 30 and 60 min and oral administration of 15 mg kg-1. Following intravenous administration the pharmacokinetics were most adequately described by a bi-exponential equation. The values (mean +/- s.e. mean, n = 20) of clearance, volume of distribution at steady-state and terminal half-life were 67 +/- 2 ml min-1 kg-1, 1.61 +/- 0.071 kg-1 and 27 +/- 1 min, respectively. Following oral administration midazolam was rapidly absorbed with a systemic availability of 45 +/- 9%. 3. The averaged amplitudes in the 11.5-30 Hz (beta) frequency band of the fronto-central lead on the left-hemisphere, as derived by aperiodic EEG analysis, was selected as a measure of the pharmacological effect of midazolam. By pharmacokinetic-pharmacodynamic modelling the individual concentration-EEG effect relationships of midazolam were derived, which were successfully quantified by the sigmoidal Emax model. No marked and systematic differences in pharmacodynamic parameters were found between the rates and routes of administration. The averaged pharmacodynamic parameters of midazolam obtained after combining the results of all rates and routes of administration were (mean + s.e.mean, n = 27): Eo = 61 + 3puV s 1, Emax = 85 + 3 Vs 1, EC50 = 40 + 3 ngmlP-1 and N = 0.84 + 0.04. 4. The results of the present study show that the concentration-EEG effect relationship of midazolam can be characterized in individual animals using the amplitudes in the 11.5-30 (beta) frequency band as a measure of pharmacological response. Acute tolerance did not develop and (inter)active metabolites did not contribute to this effect parameter within the time span of the experiments.

Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of heptabarbital using aperiodic EEG analysis

The concentration EEG effect relationship of heptabarbital was modeled using effect parameters derived from aperiodic EEG analysis. Male Wistar rats (n = 10) received an intravenous infusion of heptabarbital at a rate of 6-9 mg/kg per min until burst suppression with isoelectric periods of 5 sec or longer. Arterial blood samples were obtained and EEG was measured continuously until recovery of baseline EEG and subjected to aperiodic analysis for quantification. Two EEG parameters, the amplitudes per second (AMP) and the total number of waves per second (TNW), in five discrete frequency ranges and for two EEG leads were used as descriptors of the drug effect on the brain. The EEG parameters responded both qualitatively and quantitatively different to increasing concentrations of heptabarbital. Monophasic concentration effect curves (decrease) were found for the frequency ranges greater than 2.5 Hz and successfully quantified with a sigmoidal Emax model after collapsing the hysteresis by a nonparametric modeling approach. For the parameter TNW in the 2.5-30 Hz frequency range the value of the pharmacodynamic parameters EC50, Emax, and n (means +/- SD) were 78 +/- 7 mg/L, 11.4 +/- 1.7 waves/sec and 5.0 +/- 1.5, respectively. For other discrete frequency ranges, differences in EC50 were observed, indicating differences in sensitivity to the effect of heptabarbital. In the 0.5 +/- 2.5 Hz frequency range biphasic concentration effect relationships (increase followed by decrease) were observed. To fully account for the hysteresis in these concentration effect relationships, postulation of two effect compartments was necessary. To characterize these biphasic effect curves two different pharmacodynamic models were evaluated. Model 1 characterized the biphasic concentration effect relationship as the summation of two sigmoidal Emax models, whereas Model 2 assumed the biphasic effect to be the result of only one inhibitory mechanism of action. With Model 1 however realistic parameter estimation was difficult because the maximal increase could not be measured, resulting in high correlations between parameter estimates. This seriously limits the value of Model 1. Model 2 involves besides estimation of the classical pharmacodynamic parameters Emax, EC50, and n also estimation of the maximal disinhibition Amax. This model is a new approach to characterize biphasic drug effects and allows, in principle, reliable estimation of all relevant pharmacodynamic parameters.