Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four-way crossover design. The Digit 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 testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic 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 observed effect. The plasma-effect site equilibrium half-life was approximately 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 reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

The effects of cimetidine and ranitidine on the pharmacokinetics of cifenline.

Twelve healthy subjects completed an open single dose study to evaluate the effect of co-administration of cimetidine and ranitidine on the pharmacokinetics of cifenline. Each subject received a single 160 mg dose of cifenline alone, in combination with cimetidine (300 mg four times daily), and with ranitidine (150 mg twice daily). The H2-receptor antagonists were given with breakfast 1 h prior to cifenline dosing and continuing for 48 h. Co-administration of cimetidine significantly increased Cmax (27%) and AUC (44%) and prolonged the half-life (30%) of cifenline. There were no differences in these parameters when ranitidine was co-administered with cifenline. The results of this study suggest that cimetidine, but not ranitidine, lowers the clearance of cifenline by inhibition of hepatic oxidative metabolism.

The influence of food on the pharmacokinetics and ACE inhibition of cilazapril.

1. The influence of food on the pharmacokinetics and angiotensin-converting enzyme (ACE) inhibitory effects of oral 5 mg doses of cilazapril was investigated in a two-way crossover study in 16 volunteers. 2. Plasma and urine concentrations of cilazaprilat, the active diacid metabolite of cilazapril, and plasma ACE activity were determined by a radio-enzymatic method. 3. Cmax decreased by 30% (P less than 0.05) with a delay in (t)max of 1 h (P less than 0.05) and area under curve (AUC) was decreased by 14% (P less than 0.05). The elimination rate was unaltered. 4. Onset of ACE inhibition was delayed by approximately 30 min but degree and duration were unaffected. 5. The effect of food on the bioavailability of cilazapril at this dose would not be expected to be clinically significant.