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The following message was posted to: PharmPK
I was surprised the interest in my comments about BCS classification and the prediction of food effects yesterday. If anyone else wants a copy of the poster I mentioned, just email me off-list. But I would like to add some commentary that I did not include yesterday (that is not in the poster either):
The FDA utilizes BCS classification for regulatory purposes. Compounds classified as BCS Class 1 may undergo waivers of clinical bioequivalence studies. The FDA is very, very selective in assigning BCS 1 classification and their cutoffs in terms of in vitro permeability and solubility reflect this viewpoint. Application of the FDA classification may not be appropriate for determining other clinical properties of compounds (i.e. these permeability cutoffs may not be appropriate). I personally believe the BDCCS classification system may better reflect other clinical behavior of some compounds better than the BCS classification. But I will leave any detailed discussion of the BDCCS classification to Les Benet.
But actually I believe scientists are better off scrutinizing the actual solubility and permeability data rather than just looking at assigned classification. Does the data support where you think your compound will be absorbed? For example, I am currently reviewing the posted NDA for fingolimod. Fingolimod is very soluble in water but the distribution coefficient of fingolimod was not determined in noctanol/phosphate buffer 6.8 due to "high non-specific binding". In this case the FDA reviewer did not apply a BCS classification (and for the record I suspect this was the correct action). But for many compounds, only the solubility in water was evaluated...no consideration of pH versus pKa is ever mentioned.
Similarly the permeability data needs to be critically evaluated. Most BCS permeability studies in posted NDAs utilized Caco-2 cell systems and a handful utilized MDCK systems. There are differences in transport expression between cell systems. If you know your compound looks like a substrate for an intestinal transporter then a cell system that expresses this transporter would probably be best for predicting intestinal absorption.
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Well I can not comment on your second part of transporters, FDA BCS guidance do ask you for solubility data at pH = pKa, pka+1, pK1-2, instead of worrying about such narrow range we determine solubility at 1 degree increments between 1-14 and presented the data. The difference between BCS and BDCCS in my opinion is purely academic and in a bigger picture o drug development the differences are minor such as hair splititting, yeah I may be ruffeling egos of few individuals but I m sure majority of the people agree with me.
"For example, when the pKa of a drug is in the range of 3-5, solubility should be determined at pH = pKa, pH = pKa +1, pH = pKa-1, and at pH = 1 and 7.5. "
Hope this clarification helps. Prasad NV Tata, Ph.D.
2133 Seven Pines Drive
St. Louis, MO 63134
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