Development of in vitro/in vivo correlation for long-acting injectable suspensions via bootstrapping

In vitro/in vivo correlation (IVIVC) is of great importance to expedite the development life-cycles for pharmaceutical industry and possibly to reduce the burden for regulatory assessment, especially for long-acting injectable (LAI) drug products. However, owing to the inherent complexity and relative novelty, no regulatory guidance is available for IVIVC development of LAIs. Moreover, LAI dosage forms are prone to exhibit much higher inter-patient variability compared to conventional formulation types. Currently, relevant publications and an industry survey indicate most of the researchers tend to use mean (both in vitro and in vivo) data to establish IVIVCs, which may discount the inherent variability of LAIs, and hence may result in stringent IVIVCs with poor predictive performance. Therefore, it is critical to use statistical tools such as bootstrapping to represent highly variable in vivo pharmacokinetic profiles and more accurately develop IVIVC for various LAIs. The objective of this work is to use an innovative bootstrapping strategy for IVIVC development and evaluation to capture the inherent high inter-subject variabilities observed with four LAI aqueous suspensions. By using bootstrapping, developed IVIVC models were able to predict the in vivo performance of LAI suspensions. More importantly, it demonstrated the feasibility of using such a technique to reflect the variability of pharmacokinetic characteristics of LAI suspensions.