1 The objective of this investigation was to characterize quantitatively the in¯uence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quanti®ed by an integrated pharmacokinetic-pharmacodynamic modelling approach. 2 Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml 71 was obtained over di erent time intervals of 1 ± 6 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml 71 min 71 . In one group of rats the midazolam concentration was immediately brought to 80 ng ml 71 and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG e ect in conjunction with the decline of midazolam concentrations. 3 The increase in b activity (11.5 ± 30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG e ect could be described by the sigmoidal E max model. After placebo, the values of the pharmacodynamic parameter estimates were E max =82+5 mV, EC 50,u =6.4+0.8 ng ml 71 and Hill factor=1.4+0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC 50,u was observed with a maximum of 21+5.0 ng ml 71 at a rate of change of 0.46 ng ml 71 min 71 ; lower values of EC 50,u were observed at both higher and lower rates. 4 The ®ndings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.