The Effect of In Vivo Dissolution, Gastric Emptying Rate, and Intestinal Transit Time on the Peak Concentration and Area-Under-the-Curve of Drugs with Different Gastrointestinal Permeabilities

Abstract

Purpose. To theoretically investigate the impact of gastric emptying half-time, intestinal transit time and the time for 85% in vivo dissolution on the peak concentration and area-under-the curve of model drugs.

Methods. Simulations were performed using mathematical models of gastrointestinal physiology and pharmacokinetics of model drugs with different gastrointestinal permeability. They were used to investigate the effect of different permutations of gastric emptying times, intestinal transit times, dissolution rates and effective permeabilities on the maximum plasma drug concentration and the area-under-the-curve of immediate release tablets relative to an oral solution (i.e., Cmax_tablet/ Cmax_solution and AUC_tablet/AUC_solution).

Results. The higher the permeability of the drug, the more sensitive the Cmax ratio is to dissolution rate and gastric emptying rate. As the intestinal transit time becomes more rapid, the sensitivity to T85% dissolution time and gastric emptying half-time increases. There is less dependence for the AUC ratio on the gastric emptying time and dissolution rate.

Conclusions. Under the assumptions of the models, the criterion of 85% dissolution in 15 minutes (T85%) for classifying a rapidly dissolving drug product is relatively conservative since the Cmax ratio exceeded 0.8 for a T85% dissolution time of one hour and a gastric emptying half-time faster than 0.2 hour over a wide range of permeabilities.