Nonlinear in vitro-in vivo correlations.

Abstract

A Level A in vitro-in vivo correlation (IVIVC) has been defined as a predictive mathematical model for the relationship between the entire in vitro dissolution/ release time course and the entire in vivo response time course (e.g. the time course of the plasma drug concentration or amount of drug absorbed.)1. A definite, reproducible model across individuals would have great advantages in drug development and manufacturing2. For example, a Level A correlation can be used to establish dissolution specifications required for quality control. More recently, a Level A correlation has been proposed as a surrogate marker for human bioequivalence studies. The goal has been to obtain a linear correlation in which the profiles of in vitro and in vivo percent released versus time are parallel. Rather than achieve linearity by iteratively altering in vitro dissolution tests to match the in vivo release data or by employing other methods such as time scaling, nonlinear functions could be used to adequately predict in vivo response time course. Application of nonlinear IVIVC has been suggested by several authors3,4,5. There are a number of examples of in vitro-in vivo profiles in the literature which appear to indicate curvature and where use of a nonlinear function may be more appropriate than linear regression analysis6,7,8. This chapter outlines several nonlinear functions which could be used to characterize nonlinear IVIVC in lieu of linear regression.