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

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Abstract
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. 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%. 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 ± 3 μV s−1, Emax = 85 ± 3 μV s−1, EC50 = 40 ± 3ng ml−1 and N = 0.84 ± 0.04. 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.