BCS, IVIVC, and Bioequivalence

In-Vitro–In-Vivo Correlation, universally abbreviated IVIVC, describes a predictive mathematical relationship between an in-vitro property of a dosage form,...

In-Vitro–In-Vivo Correlation, universally abbreviated IVIVC, describes a predictive mathematical relationship between an in-vitro property of a dosage form, most commonly its dissolution or release rate, and a relevant in-vivo response, most commonly the rate or extent of drug absorption. The regulatory and scientific value of an IVIVC lies in its capacity, where sufficiently robust, to substitute in-vitro dissolution testing for costly and time-consuming in-vivo bioequivalence studies when assessing the impact of post-approval manufacturing or formulation changes, provided the correlation has been appropriately validated for the intended purpose.

The United States Food and Drug Administration recognises several levels of IVIVC, differentiated by the rigour and regulatory utility of the correlation established. A Level A correlation represents a point-to-point relationship between the entire in-vitro dissolution profile and the entire in-vivo absorption profile, and represents the highest level of correlation, capable, where properly validated, of supporting a biowaiver in lieu of an in-vivo bioequivalence study for certain SUPAC-related formulation or manufacturing changes. A Level B correlation relates summary statistical parameters — the mean in-vitro dissolution time and the mean in-vivo residence time — rather than the complete profiles, and consequently, because it is not a point-to-point relationship, offers substantially more limited regulatory utility. A Level C correlation relates a single dissolution time point, commonly the time to fifty per cent release, to a single pharmacokinetic parameter such as maximum plasma concentration or area under the curve, representing the weakest form of correlation, while a Multiple Level C correlation, relating several dissolution time points to multiple pharmacokinetic parameters, offers somewhat greater predictive value than a simple Level C correlation, though it remains inferior to a full Level A correlation.

Bioequivalence assessment, required to demonstrate that a generic or reformulated product performs comparably to a reference product, is conventionally established through a comparative pharmacokinetic study measuring the rate and extent of absorption, expressed respectively through maximum plasma concentration and area under the plasma concentration-time curve, with regulatory bioequivalence generally concluded where the 90 per cent confidence interval for the ratio of these parameters between test and reference products falls within the range of 80 to 125 per cent. Where a validated Level A IVIVC exists, or where a drug substance qualifies for a biowaiver under the Biopharmaceutics Classification System — most straightforwardly for BCS Class I compounds exhibiting both high solubility and high permeability, and, under certain additional conditions, for BCS Class III compounds — the requirement for a full in-vivo bioequivalence study may be waived in favour of comparative in-vitro dissolution testing, substantially reducing the cost, time, and, importantly, the human subject exposure associated with post-approval and generic product development.

Review Questions

1. Explain the sink condition principle and describe the pharmacopoeial dissolution media used across the physiological pH range.

2. Describe the design and operating parameters of a Franz diffusion cell IVRT study.

3. Compare the zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell release models and the mechanistic information each provides.

4. Differentiate the four levels of in-vitro–in-vivo correlation recognised in regulatory practice.

5. Explain how BCS classification and IVIVC can together support a biowaiver in place of an in-vivo bioequivalence study.