The solubility-absorption trade-off in using solubilizers: mechanistic PK simulations of progesterone with explicit cyclodextrin

Conference: World Conference on Physico Chemical Methods in Drug Discovery and Development
Software: GastroPlus®
Division: Simulations Plus


Cyclodextrins improve solubility of poorly soluble lipophilic drugs due to 1:1 complexation in their nonpolar interior cavity. However, this decreases the fraction of free dissolved drug in gut lumen and, as expected, reduces the concentration gradient for absorption across the apical membrane. This solubility-absorption trade-off was taken into account by a set of models developed by Dahan et al [1] and demonstrated on the 2-hydroxypropyl-betacyclodextrin: progesterone system. [1,2] With the 1:1 complexation equilibrium established, these implicit models calculate the boost in solubility and reduction in absorption as linear and reciprocal functions, respectively, of the cyclodextrin concentration. Sun, et al, interpreted the latter as the analytical cyclodextrin dose concentration (i.e., dose / dose volume) and fixed its value. [2] Consequently, effective solubility and permeability were fixed input parameters, as well, since the simulation system used in [2] did not track cyclodextrin evolution through the gastrointestinal (GI) tract.

By Robert Fraczkiewicz, Jin Dong, Grazyna Fraczkiewicz, and Michael B. Bolger

8th World Conference on Physico Chemical Methods in Drug Discovery and Development, September 9-11 2019, Split, Croatia