Understanding the In Vitro-In Vivo Nexus: Advanced correlation models predict clinical performance of liposomal doxorubicin

Abstract

In the century of precision medicine and predictive modeling, addressing quality-related issues in the medical supply chain is critical, with 62 % of the disruptions being attributable to quality challenges. This study centers on the development and safety of liposomal doxorubicin, where animal studies alone often do not adequately explain the complex interplay between critical quality attributes and in vivo performances. Anchored in our aim to elucidate this in vitro-in vivo nexus, we compared TLD-1, a novel liposomal doxorubicin delivery system, against the established formulations Doxil® and Lipodox®. Robust in vitro-in vivo correlations (IVIVCs) with excellent coefficients of determination (R² > 0.98) were obtained in the presence of serum under dynamic high-shear conditions. They provided the foundation for an advanced characterization and benchmarking strategy. Despite the smaller vesicle size and reduced core crystallinity of TLD-1, its release behavior closely resembled that of Doxil®. Nevertheless, subtle differences between the dosage forms observed in the in vitro setting were reflected in the bioavailabilities observed in vivo. Data from a Phase-I clinical trial facilitated the development of patient-specific IVIVCs using the physiologically-based nanocarrier biopharmaceutics model, enabling a more accurate estimation of doxorubicin exposure. This advancement could impact clinical practice by allowing for more precise dose estimation and aiding in the assessment of the interchangeability of generic liposomal doxorubicin.

Keywords: Bioequivalence; Biopredictive; IVIVC; Liposomal doxorubicin; Physiologically based nanocarrier biopharmaceutics model; Release mechanism.