In vitro–in vivo correlation for complex non-oral drug products: Where do we stand?

Abstract

In vitro–in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response of drug products. Since the U.S. Food and Drug Administration (FDA) published a regulatory guidance on the development, evaluation, and applications of IVIVC for extended release (ER) oral dosage forms in 1997, IVIVC has been one of the most important issues in the field of pharmaceutics. However, even with the aid of the FDA IVIVC Guidance, only very limited Abbreviated New Drug Application (ANDA) submission for ER oral drug products included adequate IVIVC data to enable the completion of bioequivalence (BE) review within first review cycle. Establishing an IVIVC for non-oral dosage forms has remained extremely challenging due to their complex nature and the lack of in vitro release methods that are capable of mimicking in vivo drug release conditions. This review presents a general overview of recent advances in the development of IVIVC for complex non-oral dosage forms (such as parenteral polymeric microspheres/implants, and transdermal formulations), and briefly summarizes the knowledge gained over the past two decades. Lastly this review discusses possible directions for future development of IVIVC for complex non-oral dosage forms.

Albumin‐Assisted Method Allows Assessment of Release of Hydrophobic Drugs From Nanocarriers

“…Among the in vitro release methods developed so far, the sample‐and‐separate approach is the most widely used, mainly because this methodology is simple and does not require complex apparatus . However, there are certain concerns about this approach, in particular, inability to mimic various in vivo release conditions, loss of the particles during sampling procedure, and poor hydrodynamic conditions . Membrane dialysis and flow through techniques are more sophisticated and appear to provide better mimicking of an in vivo release .…”

“…Although there is no standard or compendial approach to measure drug release from nanoparticles, several general methodologies that have been developed for characterization of drug release from polymeric microspheres can be transferable to nanomedicines. Of these, three most important approaches are: 1) sample‐and‐separate method; 2) membrane dialysis; and 3) flow through approach . None of these methods is flawless, but they have been shown to be relatively accurate providing good in vitro‐in vivo correlation in many cases …”

Nanoparticles for oral delivery: Design, evaluation and state-of-the-art

“…Models describing the relationship between an in vitro property and an in vivo response, also called an in vitro - in vivo correlation (IVIVC), have been in development since the 1950s for oral dosage forms, where the in vitro property is drug dissolution and the in vivo property is systemic pharmacokinetics [104,133,134]. Developing IVIVC models for oral nanoparticle formulations adds an additional layer of complexity in predictive modeling of drug pharmacokinetics.…”

In vitro dissolution/release methods for mucosal delivery systems

“…However, many noncompendial methods have been developed with intention to take into account the specific physiochemical properties of the formulation and the physiological environment at which the drug should be released. The goal is to develop a test able to provide predictive estimation of in vivo drug product performance, with preferably level A of in vitro-in vivo correlation (IVIVC) [4]. Development of noncompendial methodologies requires standardization of test parameters and procedures in order to ensure reproducible and reliable results.…”