NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.

The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half-time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady-state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).