The present work aims to establish a formulation-specific, physiologically based pharmacokinetic (PBPK) model for efavirenz (EFV) nanocrystals that have shown increased dissolution and were produced following a top-down approach based on wet milling and spray drying by integrating solid-state characterization, in vitro performance, and preclinical pharmacokinetics to enable translational predictions in humans. The resulting material was thoroughly characterized using diffraction-based, spectroscopic, thermal, morphological, and particle sizing techniques, along within vitro dissolution testing and an in vivo pharmacokinetic analysis in rats. Then, a fully rat PBPK model was constructed using GastroPlus and incorporating the biopharmaceutical nanoparticle properties through the product particle size distribution (P-PSD) approach. The physiologically based biopharmaceutics model (PBBM) was validated with rat in vivo data and subsequently extrapolated to simulate human physiology. Compared with unprocessed EFV, nanocrystals exhibited superior dissolution efficiency (90.4% vs 52.6%) and a more homogeneous size distribution. Furthermore, the in vivo studies confirmed an increase in EFV exposure. The rat PBPK model accurately reproduced plasma profiles of both formulations, with all predictive error metrics falling within the acceptable 2-fold range. Extrapolation to human physiology revealed that a 350 mg EFV NC dose achieved systemic exposure comparable to that of standard 600 mg immediate-release tablet, but with faster absorption. Sensitivity analyses highlighted the critical influence of particle size and bile salt solubilization capacity on EFV oral absorption. This study pioneers the application of a fully mechanistic PBPK/PBBM model tailored to nanocrystal formulations of EFV. By bridging preclinical and human data through in silico simulation, the proposed approach supports dose optimization strategies and reinforces the role of nanotechnology in advancing nonbiological complex drug development.

By Thalita Martins da Silva, Michelle Alvares Sarcinelli, Marcelo Henrique Cunha Chaves, Alan de Araújo Dias, Beatriz Ferreira de Carvalho Patricio, Livia Deris Prado, Leandro Tasso, Marcelo Dutra Duque, Helvécio V. A. Rocha