The particle drifting effect in vivo: impact of dose and animal species.

The presence of drug nanoparticles is believed to promote oral drug absorption through the particle drifting effect. These particles act as vehicles that penetrate the diffusion boundary layer adjacent to the intestinal membrane, releasing the drug near the mucosal surface, and thereby enhancing drug absorption. Despite extensive in vitro studies demonstrating the potential of this mechanism to improve drug absorption, in vivo evaluations of the particle drifting effect remain limited. In this work, we systematically evaluated the particle drifting effect in vivo in both mice and rats using enzalutamide as a model drug. To assess the impact of particle concentration, dose-escalation studies were performed to examine regions where absorption was driven by either solubilized drug or nanoparticles. The formation of amorphous drug nanoparticles was shown to significantly enhance drug absorption, confirming the role of the particle drifting effect. Nonlinear pharmacokinetics were observed in the nanoparticle absorption region, consistent with non-sink dissolution conditions in the boundary layer at high particle concentrations. Additionally, animal species-specific differences were observed, likely due to variations in bile salt concentration in the gastrointestinal fluids of mice and rats. Moreover, in vitro-in vivo relationships were established. These results provide valuable insights for early-stage formulation development, particularly for amorphous solid dispersions, before first-in-human studies where different surrogate tests and animal models are used, and should contribute to a broader understanding of how to predict the oral bioavailability of nanoparticle-containing formulations.