Liquid Biopsies or Therapeutic Drug Monitoring for CYP Activity Profile Determination

Abstract

During pharmacotherapy, knowledge about the actual drug and metabolite concentrations in plasma is often critical. Individual dose adjustments can be performed based on pre‐emptive genotyping of certain absorption, distribution, metabolism, and excretion (ADME) genes but also using therapeutic drug monitoring (TDM). Analyses of liquid biopsies for tumor‐derived components are well‐established and have been found to be a good complement to biopsy examinations. Recently, liquid biopsy‐based quantification of cell‐free RNA (cfRNA) in plasma exosomes was proposed as a proxy measurement for the expression of different hepatic ADME genes and for the rate of drug metabolism, constituting an alternative to TDM. In this study, we validated these findings by examining the correlation between mRNA expression of eight different CYP genes in liver and the corresponding rate of enzyme‐specific drug metabolism in 96 donor‐matched liver samples. Analyses of CYP‐dependent drug metabolism in liver microsomes in comparison to the level of mRNA expression for the different CYP genes revealed a mean Pearson correlation coefficient of 0.28. The highest correlations (0.33–0.34) were obtained for CYP2D6 and CYP3A4 and the weakest correlations were observed for CYP1A2 and CYP2B6 (0.18–0.21). In all cases, the correlations obtained were too weak to demonstrate a predictive relationship, likely due to different regulatory and post‐translational events controlling the rate of enzyme activity. Our results reinforce the notion that, whilst liquid biopsy‐based approaches might have utility for prediction of hepatic CYP protein expression, they are not currently an important substitute for TDM.

Is Liquid Biopsy Only Restricted to Diagnostics or Can it Go Beyond the Confines of Genotyping and Phenotyping for Quantitative Pharmacology?

“…The assumption that poor CYP mRNA-activity correlation in tissue will propagate to lack of correlation between RNA in plasma exosomes and activity is not substantiated with evidence in this report. Readers who might be perplexed by the conclusions of Pridgeon et al 1 and the counterevidence provided by our experiments 2,3 will benefit from highlighting some fundamental issues…”

“…• Poor correlation between hepatic mRNA and CYP activity, reported by Pridgeon et al, 1 is not novel. The authors might have overlooked the summary of literature on correlations (or lack thereof) between tissue mRNA and protein abundance/activity in our previous report.…”

Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine

“…These results suggest that miR-107 does not directly regulate CYP3A expression by binding to mRNA for CYP3As; rather, miR-107 may modulate the expression of multiple key transcription factors affecting P450 expression ( Tantawy et al, 2022 ). As liquid biopsy analysis of cfRNA in exosomes continues to gain interest, it is important to note that a mechanism for the association between circulating exosomal miRNA and the metabolic clearance rates of DME substrates remains largely unknown ( Pridgeon et al, 2022 ).…”

“…While the application of EVs in PK research is a relatively new field with many unknowns, growing evidence in the literature supports the use of the approach to characterize DME and transporter phenotypes in individual subjects. Recent articles have discussed the strengths and limitations of RNA-based approaches to profile DME expression using EVs ( Achour and Rostami-Hodjegan, 2022 ; Pridgeon et al, 2022 ). Achour et al (2022 ) noted that measurement of DME mRNA expression in tissue is not equivalent to expression of cfRNA in EVs due to the longer half-life of EVs and the observation that RNA in EVs has greater protection from degradation compared with cellular mRNA ( Achour and Rostami-Hodjegan, 2022 ).…”

The Broader Context of Liquid Biopsy in Absorption, Distribution, Metabolism, and Elimination

“…We read with interest the manuscript of Pridgeon and colleagues 1 entitled "Liquid Biopsies or Therapeutic Drug Monitoring for CYP Activity Profile Determination." Given the title of the manuscript it is notable that no experiments evaluating the performance of either liquid biopsy or therapeutic drug monitoring (TDM) approaches to determine cytochrome P450 (CYP) activity are described.…”