Role of In Vitro–In Vivo Correlations in Drug Development

Since the early 1950s, it was recognized that differences in dissolution and release characteristics impact in vivo systemic bioavailability resulting in therapeutic variability and in some cases toxicities and therapeutic failures (1). This resulted in considerable efforts in developing dissolution methods that can discriminate among formulations with differences in release characteristics and corresponding differences in bioavailability. On the other hand, the availability of many mathematical modeling techniques that allowed the accurate estimation of the fraction of drug released in vivo as a function of time enabled the establishment of a robust in vitro–in vivo correlation (IVIVC) that enabled the prediction of the plasma concentration–time profile of a formulation from its in vitro dissolution profile. For this reason, dissolution became a valuable tool that both the pharmaceutical industry and regulatory agencies utilize as a predictor or surrogate for bioavailability. This review article will discuss the various considerations for the establishment, evaluation, and application of IVIVC. Cases studies will be presented on the application of IVIVC to obtain in vivo bioavailability waivers as well as setting meaningful dissolution specifications that are both clinically meaningful and assure the quality of the drug product from lot to lot and from within the same lot. The cases studies will encompass both the conventional oral modified-release formulations and specialized dosage forms. In addition, common misconceptions of IVIVCs will be discussed.