An In-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response.” For pharmaceutical products (tablets and capsules in particular) development purposes, in-vitro property and in vivo response mean in vitro drug dissolution/release characteristics and the plasma drug concentration profiles, respectively.
It is important to note that this relationship, or model, always exists between the two variables (dissolution vs plasma profile) for a given drug, which forms the basis for in vitro dissolution testing and its use to assess the quality of pharmaceutical products. Therefore, developing this relationship or modeling should have never been part of the practice of drug dissolution testing or its applications for products development or evaluation. However, this is precisely what has happened during the past two decades, i.e., repeated recommendations were made for correlating dissolution results with plasma drug levels. In fact, such developments have been suggested as regulatory requirements.
A quick review of the literature will clearly show that the exercises of developing IVIVC have never been successful. Obviously, the first question would then be why has the development of IVIVC not been successful when it always exists, as stated above? One of the main reasons for such a lack of success is the choice of experimental conditions, particularly dissolution testers. The recommended dissolution testers, particularly paddle and basket, have never been shown to provide in vivo (or bio-) relevant results. That is, these apparatuses have never been qualified and validated for their intended purpose. There are reports describing that these testers cannot provide bio-relevant dissolution results. Therefore, these recommended apparatuses should have never been suggested and used for IVIVC developments. On the other hand, sporadic claims of successes of IVIVC are usually based on adjusting dissolution experimental conditions to reflect in vivo results, which by definition are not IVIVC but matching of in vitro-in vivo results, with no predictability potential. Therefore, it is often difficult to accept, but the fact remains that the current practice of IVIVC development has been a futile exercise.
The second issue with the current practice of IVIVC is that it does not predict plasma drug concentrations/profiles, which has been the promoted objective of IVIVC. As noted above, it is an approach for describing a relationship between dissolution and plasma drug profiles, but not for predicting plasma drug profiles from dissolution results. However, the latter has been assumed, unfortunately incorrectly.
It is important to note that the only objective of conducting a dissolution test is to estimate/predict plasma drug levels/profiles from dissolution results. In particular, at the product development stage, a formulator would like to estimate in vivo behavior of a test product/formulation based on drug dissolution results. This can only be achieved by combining the dissolution results of the product with the pharmacokinetic characteristics of the drug (usually available from literature). The process of combining dissolution results and pharmacokinetic parameters is known as the convolution method/technique. Thus, there is no need for developing IVIVC if the objective is to estimate/predict plasma drug levels, which indeed it is.
In short, to predict/estimate plasma drugs levels from dissolution results, one does not require IVIVC or deconvolution approach, but the convolution. Therefore, the requirement or current practice may be considered as a futile exercise, which can easily be discontinued. In addition, even for the success of the convolution approach, one would require properly qualified dissolution apparatuses, certainly, paddle and basket apparatuses in this regard are to be avoided.
To address the above-described issues, the following two suggestions have been made:
- A modified apparatus; based on currently used vessel-based apparatuses, but with a modified stirrer, known as crescent shape spindle.
- A simple convolution-based approach using Excel spreadsheet software to determine plasma drug levels from drug dissolution results.
For further details in this regard, the following links would be helpful:
- In Vitro-In Vivo Correlation (IVIVC) and Determining Drug Concentrations in Blood from Dissolution Testing – A Simple and Practical Approach. (link)
- Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation – carbamazepine. (link)
- A New Crescent-shaped Spindle for Drug Dissolution Testing—But Why a New Spindle? (link)
Presently, only the use of the crescent shape spindle provides true dissolution characteristics of a product (link)