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

Abstract

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 Fp2-M2. The EEG parameter total number of waves between 12 and 30 Hz (TNW12-30) 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 micrograms/L were obtained. Doses of midazolam 15, 30 and 60 mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 micrograms/L (session B) or 20 micrograms/L (session C), respectively. Venous blood samples were taken until 8 h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW12-30. 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 TNW12-30 (EC50) were 276 +/- 64, 624 +/- 187 and 1086 +/- 379 micrograms/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t1/2ke0), 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. Emax 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 (Cf,2) was 6.5 +/- 1.0 micrograms/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.

First Human Administration of MR04A3

“…We estimated EC 50 as 200 ng/ml and t 1/2 K e0 as 5.1 min. This t 1/2 K e0 value compares with published estimates of 1.3-4.8 min for midazolam ( 1,3,25,26 and 0.6 -3.7 min for propofol [27][28][29][30] ). Comparisons of t 1/2 K e0 across different studies are subject to methodological concerns and have limited validity.…”

Pharmacokinetic-Pharmacodynamic Relationships For Benzodiazepines

“…Four studied midazolam and/or diazepam, and were all able to fit a sigmoid E max model, with or without inclusion of an effect compartment) 13,35,37.38] One study, looking at lorazepam, used an exponential model (see table 11), [9.36) When an effect compartment was modelled, the values of V/zkeo, the half-life of equilibration (tY2keo = In2lkeo; see section 1.3), for midazolam and diazepam were less than 5 minutes, [13,37,38] indicating only a small lag time between concentration and effect. Five studies used benzodiazepine-induced EEG changes for their modelling.…”

A Response Surface Model Exploration of Dosing Strategies in Gastrointestinal Endoscopies Using Midazolam and Opioids

“…The intersession RSM is applied to the induction and washout phase. The general rule is that midazolam is given at the beginning of the induction because the onset time is approximately 3 minutes 32 and not given within 3 minutes before the end of procedure. Alfentanil and fentanyl are also not given 3 minutes before the end of procedure.…”