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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.

Thirty hypertensive patients scheduled for cholecystectomy or hernia repair under general anaesthesia with thiopentone-fentanyl-nitrous oxide-pancuronium were divided into two groups of 15. One group received metoprolol tablets 200 mg in a slow release form, once daily for at least 2 weeks including the morning of surgery. In addition, metoprolol 15 mg was injected i.v. shortly before the induction of anaesthesia. The other group received placebo tablets and saline. Two patients in the treatment group and one patient in the placebo group were subsequently excluded, because of complications during treatment. Metoprolol significantly reduced arterial pressure both during undisturbed anaesthesia, during intubation and after extubation. A similar tendency was observed also during surgery, although it was not quite significant (P = 0.055). However, metoprolol had no effect on variations in systemic vascular resistance. Mean pulmonary arterial pressures during anaesthesia and surgery were significantly greater in the control, than in the metoprolol, group. Central venous pressure (CVP) and pulmonary arterial occlusion pressure (PAOP) increased significantly in both groups in response to the surgical stimulus. There was no significant difference between the groups in PAOP and CVP. One patient in the metoprolol group had marked bradycardia (minimum heart rate 26 beat min-1) after neostigmine and atropine; otherwise metoprolol pretreatment was tolerated well.