Midazolam and flumazenil pharmacokinetics and pharmacodynamics following simultaneous administration to human volunteers.

Resedation after antagonism of midazolam sedation with flumazenil may occur because some individuals have rapid elimination of flumazenil but slow elimination of midazolam. To determine whether there are parallel or divergent rates of elimination of the two drugs between individuals, the pharmacokinetic profiles of midazolam and flumazenil were studied simultaneously in 12 adult male volunteers. Free drug concentration data for the two drugs were incorporated into a receptor occupancy model and psychomotor testing was performed and correlated with receptor occupancy. Variation was found between individuals in the pharmacokinetics of the two drugs. There were significant correlations between Cltot (P < 0.01) but not in t1/2 alpha, t1/2 beta, Vc, or VDss. In individuals, midazolam elimination half-life ranged from less than half that of flumazenil to more than three times that of flumazenil. There was a relatively poor, although statistically significant linear correlation found between calculated receptor occupancy and critical flicker fusion frequency, r = 0.50, P < 0.01, and linear analogue scales of sedation r = 0.56, P < 0.005; and anxiolysis, r = 0.54, P < 0.005. There is divergence in the disposition and elimination of midazolam and flumazenil in some individuals. A benzodiazepine receptor occupancy model is useful for predicting the consequent differences in clinical effect when the drugs are given together.