Evaluation of dose-dependent oral absorption of a newly developed drug candidate: In vitro-in vivo correlation

ONO-5129 is a dual agonist of peroxisome proliferator-activated receptors (PPARs) α and γ with poor water solubility. To assess the clinical “developability” of this drug candidate, we determined ONO-5129 maximum absorbable dose (MAD), in vitro solubility and permeability, and pharmacokinetic parameters in rats were determined. We also evaluated ONO-5129 permeation under dissolution using D/P system. Analysis of the data obtained from these predictive studies as compared to clinical pharmacokinetic data in human indicated that the D/P system was the best predictive test for non-linear oral absorption with dose increase and positive food effect. On the other hand, the prediction results of MAD underestimated absorption potential of ONO-5129 in human, while pharmacokinetic study in rat overestimated this potential. It seems that bile acid solubilization play an important role in the absorption of ONO-5129 and that the D/P system has high reproducibility for prediction of oral absorption in human intestinal tract. In case of highly lipophilic compounds with low solubility, prediction of limited oral absorption in human should be considered based on compound dissolution and permeation, both of which occur sequentially in the intestinal tract.

Effect of ONO-5129 increasing dose on oral absorption.Figure optionsDownload as PowerPoint slide