Assessing Drug Interactions Using Solute Carrier (SLC) Biomarkers: A Report from the Front Line

Date: May 12 2022
Presenter(s): David Rodrigues, PhD

Timing:

8:00 am (PT)

11:00 am (ET)

4:00 pm (GMT)

5:00 pm (CET)

6:00 pm (IST)

12:00 pm (Beijing)

01:00 am (Tokyo, Seoul)

Presenter: David Rodrigues, Ph.D., Senior Scientific Director as head of the Transporter Sciences Group at Pfizer (Groton, CT, USA)

Summary of the presentation:

It is now accepted that drug-drug interactions (DDI) involving various solute carrier (SLC) transporters are important.  Examples include statins as DDI victims involving the inhibition of hepatic organic anion transporting polypeptide (OATP1B1/3), metformin as DDI victim involving the inhibition of liver organic cation transporter (OCT) 1 (OCT1), renal OCT2 and/or multidrug & toxin extrusion pumps (MATE1/2K), and furosemide as DDI victim involving the inhibition of renal organic anion transporter (OAT) 1 and 3 (OAT1/3).  Therefore, to facilitate the study of new chemical entities as SLC inhibitors in Phase I clinical trials, numerous investigators have focused on urine- and plasma-based endogenous compounds as SLC biomarkers.  For example, plasma coproporphyrin I and III (CPI, CPIII) serve as biomarkers for liver OATP1B1/3, plasma isobutyryl-L-carnitine (IBC) can be utilized as a liver OCT1 biomarker, a perpetrator-dependent decrease in N1-methylnicotinamide (NMN) renal clearance can be used to report OCT2, MATE1, and MATE2K inhibition.  In addition, pyridoxic acid (PDA) and taurine (TAU) in plasma and urine have been described as renal OAT1 and OAT3 biomarkers, respectively.  More recently, the 3-O-glucuronide of glycochenodeoxycholic acid (GCDCA-3G) has been proposed as a selective OATP1B1 biomarker (versus GCDCA 3-O-sulfate, GCDCA-S).  The webinar will present an update regarding the deployment of such biomarkers in support of the Pfizer portfolio (blinded examples), as well as efforts to address conservative agency DDI risk cutoffs.  In the long run, it is envisioned that the bioanalysis of different biomarkers will be “multiplexed”, thus enabling multiple SLC readouts from a single blood and urine sample.  Progress will also extend to the development of physiologically based pharmacokinetic (PBPK) modeling tools facilitating in vitro-to in vivo extrapolations and the translation of clinical SLC biomarker data to drugs such as statins, metformin, and furosemide.  The webinar will also briefly cover some knowledge gaps requiring further study; do we need to address substrate-dependent in vitro IC50s? is NMN a dual OCT2-OCT1 biomarker? what SLC, if any, mediates the renal clearance of CPI and CPIII?  is CPIII an OATP2B1 biomarker?  how does GCDCA-3G compare to GCDCA-S as an ATP-binding cassette (ABC) and renal SLC transporter substrate?

Biography of the presenter:

David has been in the pharmaceutical industry for 32 years and currently holds the title of Senior Scientific Director as head of the Transporter Sciences Group at Pfizer (Groton, CT, USA).  Before joining Pfizer in 2014, he spent productive periods at other US-based pharmaceutical companies (Searle, Abbott Labs, Merck, and Bristol-Myers Squibb).  During that time, he served on both scientific and managerial ladders.  He has authored 179 peer-reviewed manuscripts, presented >85 seminars/talks/webinars, and in the past served on the editorial boards of various DMPK-related journals (Xenobiotica, Drug Metabolism & Disposition, Current Drug Metabolism). In addition, he has edited/co-edited four DMPK-related textbooks.  Presently, he serves as adjunct professor at the College of Pharmacy, University of Rhode Island, and is a member of the International Transporter Consortium (ITC). In 2009, David was inducted as Fellow of The American Association of Pharmaceutical Scientists (AAPS).  He is the recipient of the 2021 Distinguished Accomplishments in Drug Discovery & Development Award bestowed by the International Society for the Study of Xenobiotics (ISSX).