Evaluation and suggested improvements of the Biopharmaceutics Classification System (BCS)

Abstract

This review has evaluated the Biopharmaceutics Classification System (BCS) and improvements have been proposed. The BCS has a very strict solubility/dissolution limit, a generous P e -limit (≥ 14-times higher rate constant limit for dissolution than for permeation), and is stricter for drugs with a long half-life (t½). Available human in-vivo, in-vitro, and in-silico P e -methods cannot classify P e for moderately to highly permeable substances sufficiently well, and in-vitro data often underpredict the invivo dissolution potential and rate. Good in-vivo dissolution and absorption can be expected for most high P e drug products. It has not been possible to find a highly permeable product with a Dose number (D o ) < 385 (< 2400 in the fed state) that is clearly incompletely absorbed, and near complete uptake has been shown for a drug product with a D o of 660000. The potential implication of these findings is that many true BCS Class I drug products are incorrectly classified. This could be a reason for the limited use of this system. On this basis, it has been suggested that: the limit for high for solubility/dissolution is decreased (to > 40 and > 95% dissolved within 30 min and 3 h, respectively); the limit for high P e is increased (to >P e of metoprolol); accurate P e -models or in-vivo fraction absorbed data are used; solubility/dissolution tests are performed using real or validated simulated gastrointestinal fluids; in-vitro/in-vivo dissolution relationships are established; the t½ is considered; and the rate-limiting step for in-vivo absorption is determined. A major change could be to reduce the BCS into two classes: permeation-rate (Class I) or dissolution-rate (Class II) limited absorption. It is believed that this could give a better balance and increase the number of biowaivers.

The Use of BDDCS in Classifying the Permeability of Marketed Drugs

“…We agree with this proposed change, but here until a regulatory modification is implemented, we propose that the same percentage criteria be adopted for extent of metabolism as holds for extent of absorption. Although others have suggested modifying the FDA dissolution criteria, particularly for acidic drugs (23,24), we continue to support the present BCS dissolution criteria. That is, for biowaiver consideration of the dosage form, the dissolution profile of the test product must be similar to the dissolution profile of the reference product under pH 1.2, 4.5 and 6.8 conditions.…”

Application of Absorption Modeling to Predict Bioequivalence Outcome of Two Batches of Etoricoxib Tablets

“…WHO has adopted this recommendation for BCS IIa compounds (13). Similar concepts and use of PBPK models have been used to argue for further modifications to the BCS system including expansion of the solubility criteria for BCS I compounds (14) or the application of the biowaivers for BCS III compounds (15).…”

The Role of Permeability in Drug ADME/PK, Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans

“…Limitations with the BCS include a very strict solubility/ dissolution limit (and thereby incorrect classification of many in vivo Class I products into Class II), a generous P e -limit (Q14-times higher rate constant limit for dissolution than for permeation), strictness for drugs with long half-life (t 1=2 ), poor performance of human in vivo, in vitro, and in silico P emethods to classify the P e for moderately to highly permeable substances, and underprediction potential of in vivo dissolution (6). In contrast to the number of substances in BCS Class II [about 1/3; (5)] it has only been possible to clearly find/define a few highly permeable drug products with solubility/dissolution-limited GI uptake in humans (out of more than 70 drug products) (6).…”

“…In contrast to the number of substances in BCS Class II [about 1/3; (5)] it has only been possible to clearly find/define a few highly permeable drug products with solubility/dissolution-limited GI uptake in humans (out of more than 70 drug products) (6). These are danazol, and griseofulvin and atovaquone in the fasted state.…”

“…These are danazol, and griseofulvin and atovaquone in the fasted state. Ways to improve the BCS have recently been suggested (6). The BCS and BDDCS share the strictness on solubility/dissolution.…”