The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers.
OBJECTIVE
Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds.


METHODS
Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients.


RESULTS
The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher.


CONCLUSIONS
The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.
GlaxoSmithKline Inc., Research Triangle Park, North Carolina, 27709, USA.
Alan
A
Parr
Absorption Systems LP, Exton, Pennsylvania, 19341-2556, USA.
Ismael J
IJ
Hidalgo
Absorption Systems LP, Exton, Pennsylvania, 19341-2556, USA. cbode@absorption.com.
Chris
http://orcid.org/0000-0003-3074-9920
C
Bode
US Pharmacopeial Convention, Rockville, Maryland, 20852, USA.
William
W
Brown
Teva Branded Pharmaceuticals R&D Inc., West Chester, Pennsylvania, 19380, USA.
Mehran
M
Yazdanian
P'Kinetics International, Inc., Pembroke Pines, Florida, 33027, USA.
Mario A
MA
Gonzalez
Pfizer Global Research and Development, Groton, Connecticut, 06340, USA.
Kazuko
K
Sagawa
GlaxoSmithKline Inc., Research Triangle Park, North Carolina, 27709, USA.
Kevin
K
Miller
Food and Drug Administration, Office of Generic Drugs, Silver Spring, Maryland, 20841, USA.
Wenlei
W
Jiang
US Pharmacopeial Convention, Rockville, Maryland, 20852, USA.
Erika S
ES
Stippler
D000465:Algorithms; D000818:Animals; D001702:Biopharmaceutics / Q000145:classification* / Q000592:standards*; D018938:Caco-2 Cells; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
D005079:Excipients; D013501:Surface-Active Agents; D012967:Sodium Dodecyl Sulfate
BCS class III; Caco-2; bioavailability; permeability; rat intestinal perfusion model