Comparing the Altis RepliGut Organoid System to MDCK Monolayers in Predicting the Oral Absorption of Lenalidomide

Predicting human oral drug absorption early in development remains challenging for certain drug classes when using conventional in vitro systems such as PAMPA and MDCK cell monolayers. This study compared a human jejunal intestinal organoid (Altis RepliGut) monolayer system with conventional and transporter-overexpressing MDCK cell monolayers for predicting oral absorption of lenalidomide, complemented by an in vivo pharmacokinetic study in Sprague-Dawley rats modeled using Phoenix WinNonlin. Lenalidomide was well absorbed in rats (bioavailability 68-120%), and its apparent permeability in the intestinal organoid system was roughly three-fold higher than in conventional MDCK monolayers, more consistent with its observed high in vivo bioavailability; lenalidomide was also identified as a P-gp/BCRP substrate in both systems. The findings suggest that intestinal organoid systems may better capture transporter- and paracellular-mediated permeability effects than traditional MDCK models, potentially improving early predictions of oral drug absorption.