Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements.
There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly used for drug permeability screening in industry and are also accepted as a surrogate for human intestinal permeability measurements by the US FDA to support new drug applications. Countless studies carried out in this cell line with published permeability measurements have enabled the development of many in silico prediction models. We identify several common cases that illustrate how using Caco-2 permeability measurements in these in silico and in vitro predictive models will not correlate with human intestinal permeability and will further lead to inaccuracies in these models. We provide guidelines and recommendations for improving these models to more accurately predict clinically relevant information, thereby enhancing the drug discovery, development, and regulatory approval processes.
Department of Bioengineering & Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, 533 Parnassus Avenue, Room U-68, San Francisco, CA 94143-0912, USA.
Caroline A
CA
Larregieu
Leslie Z
LZ
Benet
D018938:Caco-2 Cells; D003198:Computer Simulation; D017277:Drug Approval / Q000379:methods*; D055808:Drug Discovery / Q000379:methods* / Q000592:standards; D017408:Guidelines as Topic; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011786:Quality Control; D015203:Reproducibility of Results
D004364:Pharmaceutical Preparations