In vitro in vivo correlation or IVIVC


During development of drugs and drug formulations it is important to find out whether the right drug concentration arrives at the desired place of action. It is therefore necessary to investigate the factors, which influence drug absorption into the human blood flow when a drug product is taken orally. Drug absorption is measured “in vivo”, in other words in a human (or animal) body. Typical in vivo indicators are “time – blood plasma concentration profiles” of drugs after oral administration. To identify the parameters involved in drug absorption “in vitro” investigations are usually performed. In vitro means literally “in glass” and addresses an investigation performed in an artificial environment mimicking a biological condition.





How to establish IVIVC?

To establish a reliable in vitro in vivo relationship (IVIVC) it is important that the artificial environments simulate the biological conditions as closely as possible. On that basis the experimental results can directly be connected to real outcomes in humans. During drug development and formulation exploration in vitro solubility and dissolution should artificially mimic the in vivo drug or formulation performance in the human gastrointestinal tract. The in vitro results are then related to in vivo drug plasma concentration profiles (see danazol example below). When an in vitro in vivo correlation is established, it is used for development and optimisation of drug formulations. Research organisations often use this method to reduce costly and time intensive trials on animals and humans during formulation development.





Nowadays computer models are often used to link in vitro results with in vivo outcomes. These so-called physiologically based pharmacokinetic (PBPK) models are capable of translating in vitro results into in vivo predictions. This method is defined as in vitro in silico in vivo correlation (IVISIVC).

Use of biorelevant in vitro methods

Establishing in vitro in vivo correlations for poorly soluble drugs (also referred as BCS class II and IV) can be challenging. When it comes to investigating drug dissolution performance in the simulated conditions of the gastrointestinal tract, simple buffers usually are not sufficient enough. In this case biorelevant media should be utilized, because they closely mimic the fluids of the human (and animal) stomach an intestine. Therefore biorelevant media have become the gold standard for IVIVC and IVISIVC investigations of poorly soluble drugs during formulation development. For further reading find relevant publications below.

Publications

Jennifer B Dressman and C Reppas.: In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs (2000)

Edmund Kostewicz et al.: In vitro models for the prediction of in vivo performance of oral dosage forms (2014)

Edmund Kostewicz et al.: PBPK models for the prediction of in vivo performance of oral dosage forms (2014)

Keiichi Otsuka et al.: Coupling biorelevant dissolution methods with physiologically based pharmacokinetic modelling to forecast in-vivo performance of solid oral dosage forms (2013)