Determining Drug Substance Permeability Class

The permeability class of a drug substance can be determined in human subjects using mass balance, absolute BA, or intestinal perfusion approaches. Recommended methods not involving human subjects include in vivo or in situ intestinal perfusion in a suitable animal model (e.g., rats), and/or in vitro permeability methods using excised intestinal tissues, or monolayers of suitable epithelial cells. In many cases, a single method may be sufficient (e.g., when the absolute BA is 90% or more, or when 90% or more of the administered drug is recovered in urine). When a single method fails to conclusively demonstrate a permeability classification, two different methods may be advisable. Chemical structure and/or certain physicochemical attributes of a drug substance (e.g., partition coefficient in suitable systems) can provide useful information about its permeability characteristics. The sponsors may wish to consider use of such information to support further a classification.

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