A Top-Down Physiologically Based Pharmacokinetic Modeling Approach to Explore Unexpected Bio-inequivalence of...

A physiologically based pharmacokinetic (PBPK) modeling approach was used to explore potential reasons for the unexpected in vivo/in vitro inconsistencies previously observed in an investigation exploring the comparative oral bioavailability and in vitro dissolution of three experimental treatments. All treatments contained two poorly soluble drugs: ivermectin (IVM) and praziquantel (PRZ). The purpose of that investigation was identification of alternative (non-terminal animal studies) pathways for assessing the bioequivalence (BE) of non-systemically available, locally acting oral formulations.

Treatment differences in gastrointestinal (GI) IVM and PRZ in vivo dissolution and absorption were examined using the GastroPlus PBPK software. Drug models included Michaelis Menten kinetics and canine-specific relative abundances of the primary metabolizing enzyme and efflux transporter. Individual dog predictions were generated using a top-down approach where a double or triple Weibull function was fitted to the previously generated in vivo data (27 dogs × 3 treatments = 81 profiles per drug).

By examining the predicted treatment differences in in vivo performance, it was possible to exclude several previously proposed reasons for the unexpected poor performance of one of the treatments (e.g., IVM precipitation or intestinal efflux, unintended excipient effects, and rapid dissolution increasing PRZ exposure to enterocyte Cyp3a12) for the unexpected poor performance for one of the treatments.

The top-down approach provided insights into the intestinal location of in vivo dissolution and absorption, eliminating previously proposed causes  and raising alternative possibilities for the observed in vivo/in vitro disparities (indirectly related to the granule diameters of the three treatments). It also helped identify in vitro test procedures worthy of future consideration.