Demonstration of discriminatory power and prediction of <i>in vivo</i> behaviour of complex liposomal injectable formulation using physiologically based pharmacokinetic modeling

In this current work, a generic complex liposomal injectable formulation was developed. During dossier review, a regulatory agency requested to evaluate the <i>in vivo in vitro relationship</i> (IVIVR) and the discriminative power of dissolution media from <i>in vivo</i> perspective. Establishment of a bio predictive method and IVIVR for liposomes are challenging as <i>in vivo</i> both free and encapsulated drug are measured, while <i>in vitro</i> only free is measured. However, justification of the discriminative power of a dissolution method was made using physiologically based pharmacokinetic (PBPK) modeling. Physicochemical, biopharmaceutical, dissolution profiles and pivotal plasma profiles were integrated for model development. The dissolution profile fitted into first order kinetics and the <i>in vitro K_{in vitro}</i> _rel was used to link liposomal and free drug concentrations in the blood. Model validation was proved by predicting bioequivalence (BE) ratios that are in line with the observed BE outcome. The model was applied to demonstrate discriminatory power of dissolution method by integrating <i>K_{in vitro}</i> _rel derived from various batches. The simulated BE ratios are inline to dissolution difference and thus discriminatory power from <i>in vivo</i> perspective was demonstrated. This justification was accepted by agency and led to acceptance and product approval. This approach opened new avenues for describing <i>in vivo</i> behavior of complex intravenous liposomal formulations.