There are instances in drug development where modifications are made to a drug’s composition, formulation, equipment used, or manufacturing processes.  These modifications require reassessment of the modified product to ensure the same pharmacological behavior. When a strong in-vitro-in-vivo correlation (IVIVC) is made, it effectively serves as a surrogate to costly in vivo bioequivalence studies, for which a biowaiver must be obtained. The flexibility of a validated IVIVC saves a great deal of time and resources spent in formulation optimization.

The in vitro data set characterizes drug products in terms of release or dissolution rate, while in vivo data provides an absorption rate, or plasma concentration profile. The goal of an IVIVC is to serve as a predictive mathematical model of the relationship between data sets. A variety of formulations are necessary for a comprehensive study.

IVIVC development is an iterative process that begins with an assumed IVIVC based on in vitro targets derived from characterization of desired in vivo profile specifications, and pilot pharmacokinetic analyses, after which a retrospective IVIVC is formed. A prospective IVIVC study is designed, based on ongoing extensive in vitro characterization regarding formulations and each aspect of the development process, in order to form a definitive IVIVC.

A biowaiver is obtained by achieving validation that is graded on the strength of the IVIVC made. Level A correlation, for instance, demonstrates a point-by-point relationship between the in vivo and in vitro profiles. Level B correlation is achieved through a statistical analysis of mean values, and Level C connects one time point on the in vitro curve to a mean pharmacokinetic parameter of the in vivo input curve.

A validated IVIVC facilitates cost-effective formula optimization, which can occur at the approval, scale-up, and post-approval stages in drug development. It also improves quality assurance deliberations, including release profile characteristics that may reveal dose-dumping potential, and other important pharmacokinetic features. Successful in vitro dissolution testing as a surrogate to in vivo bioequivalence testing relies on its in vivo relevance. A quality IVIVC makes this possible.

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Categories: Toxicology and Pharmacology

Tags: drug development, in-vitro-in-vivo correlation (IVIVC), pharmacokinetic