Pharmacokinetic-Pharmacodynamic Modelling of the Interaction between Flumazenil and Midazolam in Volunteers by Aperiodic EEG Analysis

Summary

The CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp₁-M₁ and F_P2-M₂. The EEG parameter total number of waves between 12 and 30Hz (TNW_12–30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that ‘steady-state’ concentrations of 10 and 20 µg/L were obtained. Doses of midazolam 15, 30 and 60mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 µg/L (session B) or 20 µg/L (session C), respectively. Venous blood samples were taken until 8h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (E_max) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (C_em) [C_em/Kp] and TNW _12–30.

Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (± SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW 12–30 (EC₅₀) were 276 ± 64, 624 ± 187 and 1086 ± 379 µg/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t_½k_e0), estimated by a nonparametric method, were 2.2 ± 1.2, 3.3 ± 3.3 and 2.9 ± 1.2 min for the 3 different sessions. E_max and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC₅₀ of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC₅₀ of midazolam (C_f,2) was 6.5 ± 1.0 µg/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.