From Endogenous Compounds as Biomarkers to Plasma‐Derived Nanovesicles as Liquid Biopsy; Has the Golden Age of Translational Pharmacokinetics‐Absorption, Distribution, Metabolism, Excretion‐Drug–Drug Interaction Science Finally Arrived?

Abstract

It is now established that a drug's pharmacokinetics (PK) absorption, distribution, metabolism, excretion (ADME) and drug–drug interaction (DDI) profile can be modulated by age, disease, and genotype. In order to facilitate subject phenotyping and clinical DDI assessment, therefore, various endogenous compounds (in plasma and urine) have been pursued as drug‐metabolizing enzyme and transporter biomarkers. Compared with biomarkers, however, the topic of circulating extracellular vesicles as “liquid biopsy” has received little attention within the ADME community; most organs secrete nanovesicles (e.g., exosomes) into the blood that contain luminal “cargo” derived from the originating organ (proteins, messenger RNA, and microRNA). As such, ADME profiling of plasma exosomes could be leveraged to better define genotype‐phenotype relationships and the study of ontogeny, disease, and complex DDIs. If methods to support the isolation of tissue‐derived plasma exosomes are successfully developed and validated, it is envisioned that they will be used jointly with genotyping, biomarkers, and modeling tools to greatly progress translational PK‐ADME‐DDI science.

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…A recent study showed that CPI and CPIII can successfully predict strong and mild OATP1B‐mediated DDI in the clinic (Kunze, Ediage, Dillen, Monshouwer, & Snoeys, ). For detailed information on transporter biomarkers, please refer to other articles on the topic (Barnett et al, ; Chu et al, ; Chu, Chan, & Evers, ; Jones et al, ; Mariappan, Shen, & Marathe, ; Mueller, Sharma, Koenig, & Fromm, ; Rodrigues & Rowland, ; Shen, ; Yoshikado et al, ). Biomarkers are active research areas and future advances will help to provide new tools and insights to more accurately predict clinical DDIs.…”

Virtual Twins: Understanding the Data Required for Model‐Informed Precision Dosing

“…Measurement of relative changes in DMET activities with time-dependent increases and decreases in functional protein are good (i.e., induction, mechanism-based inactivation), but there is less confidence in estimating absolute abundance values. 8 3. Plasma exosomes as "liquid biopsies.…”

Come Dance With Me: Transformative Changes in the Science and Practice of Drug–Drug Interactions

“…As discussed by Mikus, appropriately qualified probes and cocktails administered in microdose studies represent one avenue for collecting such data in clinical development. Rodrigues and Rowland offer a comprehensive review of the use of tissue‐derived plasma exosomes, which can be particularly valuable in generating longitudinal data on the dynamics of effects of a drug or biologic on the expression and activity of a battery of ADME proteins via ex vivo profiling. Continued forward and reverse translational research on the proposed “liquid biopsy” framework and the incorporation of the results of such investigations into PBPK models will be crucial to quantify and assess the impact of translational gaps between the ex vivo exosomal setting and in vivo native tissue setting.…”