By Ami Patel
Transporters play a major role in the pharmacokinetic, safety, and efficacy profiles of drugs. Since 2003, the AAPS transporters workshops have constituted an excellent platform for pharmaceutical and regulatory scientists to exchange ideas, learn about cutting-edge research, and discuss personal experiences during drug development. Of all the workshops I’ve attended, this year’s event, the 2015 AAPS/ITC Joint Workshop on Transporters was the most interesting to me, as my academic and industry interests merged recently and gave me a unique perspective.
Effort is always put in by organizers to have a keynote presentation that is inspiring, connects with the attendees, and motivates change. I found this year’s keynote presentation by Geraldine A. Hamilton, Ph.D., Organs-on-Chips: Elucidating Human Response to Drugs and Disease, particularly inspiring, and it set a perfect stage and tempo for the first session, Transporter Tools of the Future. “Organs on chips” are bioengineered microenvironments that can be utilized as surrogates of the human body that incorporate tissue-tissue interfaces, biochemical cues, mechanical forces, and physiological perfusion in an organ-specific context. Liver, kidney, intestine, and lung organ chips were presented. Each of these organ chips can be connected to each other to emulate human physiology. The videos embedded in the presentation constituted the “wow factor,” by demonstrating the importance of factors such as mechanical stress and physiological perfusion on the transport properties of cells in an in vivo situation. The following talks on the liver microphysiology system and kidney-on-a-chip models reinforced the usefulness of this technology and demonstrated its key characteristics, robustness and reproducibility, and the predictivity, which are required for implementation in preclinical screening of potential compounds. Considering the commercial and regulatory challenges that the existing tools face in a still-emerging field, industry-wide use of this cutting-edge tool still has a ways to go but offers great promise.
Discussions on the current BCRP, MATE1/MATE2K, and MRP2 test systems indicated a need for improvement to make them more physiologically relevant. In addition, the importance of the function and expression of proteins related to drug ADME was highlighted throughout various talks. The accurate quantification of the ADME proteins in the existing test systems is fundamental in establishing IVIVE for pharmacokinetic predictions. This is an immediate need as it has implications on in vitro concentration choices that can then be scaled based on the transporter expression of the test system and better correlate transporter activity and drug disposition.
Other inspirational discussions revolved around characterization of novel transporters such as NPC1L1 in the Caco-2 cell model, development of OSTα/β knockout cell lines, and emphasis on the importance of OATP2B1, NTCP, OAT2, and MRP2/4 transporters.
In all, we all left the workshop with some insights, questions, and homework, and I look forward to attending the 2016 workshop for some answers and updates, in addition to learning about the future hot topics.