Dose staggering as a strategy to reduce drug--drug interactions due to reversible enzyme inhibition between orally administered drugs with high first pass effect: a computer simulation study.

A physiological computer model was designed to simulate the metabolic drug–drug interactions between two orally co-administered drugs due to reversible enzyme inhibition using drug concentrations in the portal vein. The extent of interactions was compared at steady-state for the effects of a delay in time between the administration of the substrate and the inhibitor. It was demonstrated that the extent of the interactions can be strongly affected by a time interval between the two drug administrations. By delaying the administration of the inhibitor until after the absorption phase of the substrate, one can significantly reduce the extent of the drug–drug interactions. This is because drug concentrations in the portal vein and the liver are much higher than that in the systemic circulation during the absorption phase. The model also showed that interactions involving substrates with a high extraction ratio (EH), i.e., drugs with higher first-pass effect, can be more strongly affected by dose staggering. Substrates with a low absorption rate constant (ka) require a longer interval with the inhibitor in order to reduce the extent of the interactions. This observation suggests dose staggering as a simple and cost-effective way to reduce the extent of unwanted drug–drug interactions in clinical practice. Copyright © 2000 John Wiley & Sons, Ltd.