Liquid Biopsy Approaches to Support Clinical Drug
Interaction Assessment & Subject Phenotyping

David Rodrigues, PhD
ADME Sciences, Medicine Design, Pfizer, Groton CT USA

David has been in the pharmaceutical industry for 31 years and currently holds thetitle of Senior Scientific Director as head of the Transporter Sciences Group at Pfizer(Groton, CT).

Before joining Pfizer in 2014, he spent productive periods at Searle, Abbott

Labs, Merck, and Bristol-Myers Squibb.

During that time, he served on both scientific(Associate Research Fellow, Senior Research Fellow) and managerial (Director, SeniorDirector, Executive Director) ladders.
He has authored over a dozen book chapters, 170 peer-reviewed manuscripts, haspresented at >80 venues (scientific symposia/meetings/webinars), and served on theeditorial boards of various DMPK-related journals (e.g., Current Drug Metabolism, Drug

Metabolism Letters, Xenobiotica, Drug Metabolism & Disposition). In addition, he hasedited/co-edited three text books related to drug interactions and one on the topic of drug
metabolism.

Presently, he is a member of the International Transporter Consortium(ITC) and also serves as adjunct professor at the College of Pharmacy, University of RhodeIsland. In 2009, David was inducted as Fellow of The American Association of
Pharmaceutical Scientists (AAPS).
Over the last 5 yrs, David has worked extensively with colleagues in Japan (PfizerTokyo, Prof. H. Kusuhara at University of Tokyo, Prof Y. Sugiyama at The Riken Institute,and Dr. K. Furihata at the P-One Clinic) to advance transporter biomarker research.
More recently, such transporter biomarker efforts have included the laboratory of Prof. M.
Niemi (University of Helsinki, Finland).

Presently, his research has also extended toFlinders University (A. Rowland lab, Adelaide, Australia), which has involved theexploration of serum- and plasma-derived EV as liquid biopsy.
Endogenous Probes for Drug Transporters: Balancing Vision With Reality. Rodrigues AD, Taskar KS,Kusuhara H, Sugiyama Y. Clin Pharmacol Ther. 2018 Mar;103(3):434-448.
PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibitionof Hepatic OATP1B1 and OATP1B3. Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues
AD, Chiba K, Sugiyama Y. CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):739-747.
Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion
Protein-Mediated Drug-Drug Interactions in Healthy Volunteers. Miyake T, Kimoto E, Luo L, Mathialagan
S, Horlbogen LM, Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, Rodrigues AD, Muto C,
Furihata K, Sugiyama Y, Kusuhara H. Clin Pharmacol Ther. 2021 Feb;109(2):507-516.
Dose-Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation ofCandidate Biomarkers and OATP1B Probe Drugs. Mori D, Kimoto E, Rago B, Kondo Y, King-Ahmad A,Ramanathan R, Wood LS, Johnson JG, Le VH, Vourvahis M, David Rodrigues A, Muto C, Furihata K,Sugiyama Y, Kusuhara H. Clin Pharmacol Ther. 2020 Apr;107(4):1004-1013.
Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly
Sensitive and Specific OATP1B1 Biomarkers. Neuvonen M, Hirvensalo P, Tornio A, Rago B, West M, Lazzaro
S, Mathialagan S, Varma M, Cerny MA, Costales C, Ramanathan R, Rodrigues AD, Niemi M. Clin Pharmacol
Ther. 2021 Mar;109(3):646-657.

Various clinical tools have been developed to support the study of genotypephenotype associations and drug-drug interactions (DDI) involving drugmetabolizing enzymes (e.g., cytochromes P450, CYP) and drug transporters.
These have included probe drugs, probe drug cocktails, micro-dosing, tissue
imaging reagents, and endogenous compounds in plasma and urine that present
as biomarkers. More recently, attention has turned to “liquid biopsy” methods,
which involve the profiling (proteomics and CYP activity) of immunocaptured
cargo-laden and tissue-specific extracellular vesicles (EV) present in human blood.
The presentation will describe the isolation, characterization, and profiling ofserum EV (mixtures of exosomes and small microvesicles) in support of CYP andorganic anion transporting polypeptide (OATP) profiling. Examples include
CYP2D6 genotype-phenotype associations, CYP3A5 genotype-liver protein
expression profiling, differentiation of gut CYP1A2 versus CYP3A4 activity,induction profiling (liver CYP3A4, CYP2D6, OATP1B1, and OATP1B3) followingan inducer (rifampicin), and expression profiling of serum-derived liver EV frompregnant versus non-pregnant females. With further validation and wider use,
it is envisioned that the EV-based liquid biopsy approach will be deployed
alongside established drug probe-based methods and emergent drug transporterbiomarkers. Such advancements are warranted because of the absence of CYP
biomarkers (beyond CYP3A4/5), increasingly complex DDI involving gut and/or
liver CYP3A4/5, and questions regarding transporter induction.
Plasma extracellular nanovesicle (exosome)-derived biomarkers for drug metabolism
pathways: a novel approach to characterize variability in drug exposure. Rowland A,Ruanglertboon W, van Dyk M, Wijayakumara D, Wood LS, Meech R, Mackenzie PI,
Rodrigues AD, Marshall JC, Sorich MJ. Br J Clin Pharmacol. 2019 Jan;85(1):216-226.
Profiling of Drug-Metabolizing Enzymes and Transporters in Human Tissue Biopsy
Samples: A Review of the Literature. Rodrigues AD, Rowland A. J Pharmacol Exp Ther.
2020 Mar;372(3):308-319.
Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides:
Where Is the Evidence for Its Relevance in Drug-Drug Interactions? Rodrigues AD, Lai Y,Shen H, Varma MVS, Rowland A, Oswald S. Drug Metab Dispos. 2020 Mar;48(3):205-216.
From Endogenous Compounds as Biomarkers to Plasma-Derived Nanovesicles as LiquidBiopsy; Has the Golden Age of Translational Pharmacokinetics-Absorption, Distribution,Metabolism, Excretion-Drug-Drug Interaction Science Finally Arrived? Rodrigues D,Rowland A. Clin Pharmacol Ther. 2019 Jun;105(6):1407-1420.

Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy toStudy the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting
Polypeptides. Rodrigues AD, van Dyk M, Sorich MJ, Fahmy A, Useckaite Z, Newman LA,Kapetas AJ, Mounzer R, Wood LS, Johnson JG, Rowland A. Clin Pharmacol Ther. 2021
Apr 1. doi: 10.1002/cpt.2244. Online ahead of print