An additive or synergistic drug interaction: application of concentration-effect modeling

Although a conventional pharmacokinetic analysis can identify the pharmacokinetic component in a drug interaction, the pharmacodynamic component is less accessible and, ideally, should be evaluated over a range of doses. The potential of integrated concentration-effect modeling to avoid such multiple-dose studies has been evaluated in this study of the hypotensive effect of the combination of prazosin and verapamil, which has previously been shown to be more than simply additive. Characterization of the blood pressure responses (by concentration-effect modeling) revealed that for supine diastolic blood pressure, responsiveness was significantly higher at 3.3 +/- 0.5 mm Hg per ng/ml when prazosin was combined with verapamil (p less than 0.01) compared with 2.4 +/- 0.5 and 2.4 +/- 0.4 mm Hg per ng/ml, respectively, for standard doses and augmented doses of prazosin alone. These findings suggest that there are both pharmacokinetic and pharmacodynamic components in the interaction between prazosin and verapamil and illustrate the applicability of concentration-effect modeling for investigating drug interactions.