John Gleeson
Senior Scientist
Merck
Talk Information
Strategies for Membrane Permeability or Oral Bioavailability
, 08:30am - 08:55am, in the Pacific Jewel Ballroom
L02 – Development, Validation, and Implementation of Intestinal Cell Models to Guide Oral Peptide Formulation Design
Dr. John P. Gleeson is a Senior Scientist in Biopharmaceutics at Merck & Co., Inc., where he supports the development of oral drug formulations and leads research in predictive in vitro intestinal absorption models.
Academic Background
Dr. Gleeson earned his B.Sc. in Nutraceuticals in Health and Nutrition from Technological University Dublin in 2012. He completed his Ph.D. in Intestinal Physiology and Pharmacology at University College Dublin in 2017, focusing on intestinal permeation enhancers for oral drug delivery.
Professional Experience
Following his doctoral studies, Dr. Gleeson pursued postdoctoral research at Cedars-Sinai Medical Center, investigating induced pluripotent stem cell-derived intestinal organoids as models for inflammatory bowel disease. He then continued his postdoctoral work at Carnegie Mellon University, exploring oral drug delivery and the therapeutic potential of breast milk cells.
Research Focus
At Merck, Dr. Gleeson specializes in developing predictive in vitro models to assess intestinal absorption of oral drug formulations. His expertise includes oral drug delivery, permeation enhancers, and intestinal absorption of drugs, nutrients, and cells.
Notable Contributions
Dr. Gleeson has authored or co-authored over 20 research articles, contributing significantly to the fields of biopharmaceutics and drug delivery.
Professional Engagements
Beyond his research, Dr. Gleeson co-leads the Inclusion team in Pharmaceutical Sciences and Clinical Supply at Merck, promoting diversity and inclusion within the organization.
Through his interdisciplinary research and leadership, Dr. John P. Gleeson continues to advance the development of oral drug formulations and predictive absorption models in the pharmaceutical sciences.
Development, Validation, and Implementation of Intestinal Cell Models to Guide Oral Peptide Formulation Design
Exploratory Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., Rahway, New Jersey, USA
Oral delivery is the most patient-preferred route of drug delivery, especially for chronic disease treatment. Predicting the clinical performance of BCS Class III and IV drugs including oral peptides is difficult due to their low intestinal permeability and limitations of current in vitro and in silico models.
The Caco-2 Transwell model is the gold standard for permeability assessment, as per FDA and ICH guidance; however, it has poor predictability for low permeability compounds and permeation enhancer efficacy that are often required in oral peptide formulations. To improve the predictability of these models, we took a number of approaches: (1) utilizing a microfluidic Chip platform instead of Transwell, (2) adapting the cellular source from Caco-2 to biopsy-derived organoids, and (3) improving the buffers and matrices overlaid on cells to mimic physiological conditions.
We validated the clinical predictability of a Caco-2 Chip model using 19 small molecule drugs (r2 = 0.71) compared to conventional Transwells (r2 = 0.76), and assessed permeation enhancer efficacy (sodium caprate and sucrose monolaurate). The Chip model showed more modest enhancement (2-fold and 8-fold) versus Transwells (10-fold and 150-fold), in line with preclinical and clinical observations.
Biopsy-derived organoids are an emerging tool to better recapitulate the intestine, as they are said to retain their regional specificity. However, in ileum and colon matched samples, we observed only one donor of three with expected regional size-based permeability (ileum Papp > colon Papp) to macromolecules, and equivalent permeability (ileum Papp = colon Papp) to BCS I and II drugs in both Transwells and Chips, platform independent. Our approach has enabled us to triage formulations and peptides using cell-based platforms prior to preclinical species to improve outcomes and success toward the clinic.