An in vivo/in vitro correlation (IVIVC) adds in vivo relevance to in vitro dissolution specifications. With this correlation model, the in vitro dissolution test can be used to predict the in vivo performance of the formulation.
Applications of IVIVC
The main objective is to establish the dissolution test as a surrogate for human bioequivalence studies in the initial approval process, the scale-up process, and for post-approval changes. When requesting biowaivers for changes in the drug manufacturing, IVIVC can be used in lieu of required in vivo studies. It also can be used in setting dissolution specifications. Examples also include supporting strength change justification, supporting Formulation Development and Batch-to-Batch quality control etc.
Discover Expected Bioavailability for ER Drugs with an IVIVC
Although the FDA Guidance is nearly 20 years old, “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations”remains the definitive authority on the subject.
The recommendations cover in vitro/in vivo correlation for an oral extended release (ER) drug product used in conjunction with submitting a new drug application (NDA), an abbreviated new drug application (ANDA) or an antibiotic drug application (AADA). Between 2009-2012, 89% of regulatory submissions containing IVIVC models were NDAs.[i]
The guidance outlines ways to develop an IVIVC and evaluate predictability, use an IVIVC to establish specifications for dissolution and apply an IVIVC as a surrogate for in vivo bioequivalence. The ability to accurately and precisely, predict expected bioavailability characteristics for an ER product from dissolution profile characteristics has been a long sought after goal, according to the guidance.
Categories of IVIVC
There are three foundational levels of IVIVC, Level A, Level, B and Level C. It was recorded that 74% of investigational and new drug applications between 2009-2012 were Level A[ii]. Whereas, Level B submissions are rarely seen, as are Multiple Level C submissions. However, Level C can be useful in the early stages of development
- Level A: Generally, a linear point-to-point relationship between in vitro dissolution and the in vivo input rate.
- Level B: Mean in vitro dissolution time (MDT) vs. mean residence time in vivo (MRT).
- Level C: Single point relationship. e.g. t50%, % dissolved in 4 hours vs. PK Pars (AUC, Cmax, Tmax).
- Multiple Level C: Relates one or several PK parameters of interest to drug dissolved at several time points.
Sample sizes for these types of studies should be between 6 and 36, and only human data is permitted. Crossover studies are preferred, but parallel studies may be found acceptable by the FDA. The reference product to develop an IVIC can be intravenous, immediate release or an aqueous oral solution. Although a fasting state is preferred, a fed state may be acceptable for safety reasons.
FDA guidance suggested that two or more formulations with different release rates (e.g. differ by 10% as measured by percent dissolved of slow, medium and fast release formulations) should be used in demonstrating IVIVC relationship. Use of only one formulation may be considered for formulations for which in vitro dissolution is independent of the dissolution test conditions (e.g., medium, agitation, and pH).
According to the guidance, “The model should predict the entire in vivo time course from the in vitro data. In this context, the model refers to the relationship between in vitro dissolution of an ER dosage form and an in vivo response such as plasma drug concentration or amount of drug absorbed.”
Level C is a single-point relationship but is not useful for obtaining a bioequivalence waiver. Multiple Level C may be useful with at least three dissolution time points covering the early, middle, and late stage of the dissolution profile. If a Level C is achievable, a Level A correlation is likely and is the preferred submission method. Developing and evaluating the correlation use the same criteria as with Level A correlation.
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