Making ADME your BFF
How many of you, like me, remember the first time you heard of the acronym ADME?
“Add me to what?” I was perplexed as a neurobiologist uninitiated in pharmacological jargon. By now of course, I have learned ADME stands for Adsorption, Distribution, Metabolism, and Excretion. According to Luke Lightning, however, it’s not enough to just know the WHAT of ADME; you need to also know the WHEN, WHERE, and HOW. If you’re interested in pre-clinical drug development, you’d better make sure ADME is your BFF.
Lightning, Senior Director of Research at Alquest Therapeutics, spoke at the symposium “If only I’d known about preclinical drug development,” hosted by QB3 and co-sponsored by Patheon and Deloitte Consulting LLP. He argues that the importance of ADME cannot be overstated, because it allows you to learn more about your candidates, and informs go vs. no-go decisions.
Keep in mind that multiple in vitro and in vivo ADME approaches are available. In vitro studies include metabolic stability, drug-drug interaction, induction, permeability, and transporters. In vivo experiments investigate pharmacokinetics and dose formulation. In deciding whether to perform ADME studies in-house or through outsourcing, a myriad of factors need to be considered, including financial reasons, granting agencies, personnel, and equipment.
Conducting ADME studies in-house offers direct oversight, but the hefty price tag of hiring specialized personnel and purchasing equipment could be a deterrent. With flexibility, repeatability, and fast turnaround time, outsourcing to Contract Research Organizations (CROs) serves as an attractive alternative. Given the differentials on price and scope of service, finding the CRO that fits your need could be a daunting task. Dr. Lightning recommends two useful online databases to facilitate your search: Assay Depot and Science Exchange. Assay Depot contains a database of CROs worldwide with information on pricing and protocols. Science Exchange operates similarly but also includes a list of universities that can provide services.
Here is a simple example of ADME work plan provided by Lightning. He suggests initially starting with some exploratory, non-GLP experiments to get a quick idea of the ADME profile of your compounds and help select candidates for further studies. For example, select ten compounds for in vitro experiments in singlet instead of triplicate to drive down cost. These may include plasma protein binding and blood stability, as well as metabolic stability in liver microsomes. From there, you can select two to three compounds for rodent pharmacokinetics and CYP3A4 inhibition experiments, move them on to efficacy studies after evaluation, and then repeat the process. In the end, you will obtain two to three promising candidates for more in-depth ADME analysis run in triplicates.
Fast iteration is key to the lean startup model, he says.
Check out Lightning’s slides here for a wealth of tips and links. The pre-clinical drug development symposium, held last Friday at UCSF Mission Bay, also featured presentations and panel discussion by other industry leaders and academic experts, covering topics ranging from CMC, ADME, toxicology, to drug development partner selection and sources of funding. More slides are distributed via our podcast feed.