Pharmacodynamic model for acute tolerance development to the electroencephalographic effects of alfentanil in the rat

This investigation was carried out to characterize the rate and extent of acute tolerance development to the pharmacodynamics of alfentanil in the rat with the electroencephalogram (EEG) as a measure of alfentanil's effects on the central nervous system. Alfentanil was administered by use of three different drug infusion strategies in order to develop a pharmacokinetic-pharmacodynamic model for acute tolerance: I) intravenous infusion of 0.5 mg/kg in 10 min, achieving peak alfentanil concentrations of 750 ng/ml; II) computer-controlled infusion to rapidly achieve and maintain a constant drug level of 750 ng/ml, followed by washout; III) computer-controlled infusion to step through multiple constant drug levels (up to 1500 ng/ml), followed by washout. Frequent arterial plasma samples were taken and assayed for alfentanil. EEG signals were continuously recorded until effects returned to base-line values. The amplitudes in the 0.5- to 3.5-Hz (delta) frequency band were calculated by aperiodic analysis and used as an EEG effect measure. The pharmacokinetic data were characterized by a three-compartment model with nonlinear clearance. Nonlinear kinetics was apparent from the multiple steady-state protocol III. Clearance values ranged from (S.E.) 49.7 (2.8) ml/min/kg at low alfentanil concentrations to a minimum value of 29.3 (0.8) ml/min/kg at high concentrations. The pharmacodynamic data showed profound acute tolerance development reflected as proteresis in the concentration-effect pairs after protocol I and a rapidly declining effect in the presence of stable alfentanil concentrations after protocols II and III. The effect stabilized within 15 min after a change in target concentration. A physiological tolerance model was developed to characterize the rate and extent of tolerance development to the effects of alfentanil. The models are generally applicable and consider the physiological homeostatic mechanisms responsible for the tolerance development to be an integral part of the pharmacodynamic system. Tolerance was modeled as a negative feedback control of the drug-induced effect with a first-order transfer function. The model required only two tolerance parameters to quantify the rate and extent of tolerance development and allowed for a rebound effect. Maximum tolerance diminished alfentanil's effect by 46% and was achieved with a half-life of 7.0 min.