SIMULTANEOUS MODELING OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OFMIDAZOLAM AND DIAZEPAM

The pharmacokinetics and pharmacodynamics of midazolam and diazepam we re compared after intravenous infusions of 0.03 and 0.07 mg/kg midazol am and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 hea lthy male subjects in a randomized four-way crossover design, The Digi t Symbol Substitution Test (DSST) was used as a measure of drug effect , Subjects performed three practice tests before dosing to account for any effects caused by familiarization (''learning curve'') with the t esting procedure, Pharmacokinetic and pharmacodynamic data were simult aneously fined to a semiparametric model, In this model, a pharmacokin etic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the obs erved effect, The plasma-effect site equilibrium half-life was approxi mately 2 1/2 times longer for midazolam than for diazepam, which is in good agreement with previously published data, Based on the estimated effect site concentration at which half of the maximal effect was rea ched, midazolam had approximately a sixfold greater intrinsic potency than diazepam, This difference in potency was also observed in a previ ous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity, The findings reported here with a cli nically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the f easibility of conducting pharmacokinetic pharmacodynamic analysis duri ng the drug development process.