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The pharmacokinetic‐pharmacodynamic (Digit Symbol Substitution Test) relationship of flumazenil in a midazolam steady‐state model in healthy volunteers
Author(s) -
Zhi Jianguo,
Massarella Joseph W,
Melia Angela T,
Teller Stuart B,
SchmittMuskus Janet,
Crews Theodore,
Oldfield Neil,
Erb Randall J,
Leese Phillip T,
Patel Indravadan H
Publication year - 1994
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1994.174
Subject(s) - flumazenil , digit symbol substitution test , midazolam , pharmacokinetics , pharmacodynamics , placebo , anesthesia , pharmacology , crossover study , medicine , antagonist , chemistry , sedation , receptor , alternative medicine , pathology
To characterize the plasma concentration–effect relationship of flumazenil in the presence of a predefined midazolam level, a double‐blind, placebo‐controlled, randomized two‐way crossover study was conducted in nine healthy male subjects. After reaching a criterion level of midazolam‐induced depression of the Digit Symbol Substitution Test (DSST), volunteers received a dose of flumazenil (1.0 mg) or placebo over 1 minute, with the infusion of midazolam continued. Blood samples were collected, simultaneously with the DSST assessment, at predetermined intervals and were assayed for flumazenil and/or midazolam plasma concentrations. Pharmacokinetic‐pharmacodynamic modeling techniques were used to estimate the equilibration rate constant (k eo ) between plasma concentration and effect for flumazenil; a sigmoidal maximum‐effect model was used to relate the DSST score to the flumazenil plasma concentration. Flumazenil exhibited a rapid onset (the half‐life of equilibration between drug concentration in the blood and drug effect was 3.3 minutes) and short duration of action (the flumazenil plasma concentration causing half‐maximal effect was 7.4 ng/ml, which was reached about 1 hour after dosing). The results of this study also show the competitive nature of flumazenil as a midazolam antagonist. Clinical Pharmacology and Therapeutics (1994) 56, 530–536; doi: 10.1038/clpt.1994.174