Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine

Abstract

Pharmacometabolomics (PMx) studies use information contained in metabolic profiles (or metabolome) to inform about how a subject will respond to drug treatment. Genome, gut microbiome, sex, nutrition, age, stress, health status, and other factors can impact the metabolic profile of an individual. Some of these factors are known to influence the individual response to pharmaceutical compounds. An individual’s metabolic profile has been referred to as his or her “metabotype.” As such, metabolomic profiles obtained prior to, during, or after drug treatment could provide insights about drug mechanism of action and variation of response to treatment. Furthermore, there are several types of PMx studies that are used to discover and inform patterns associated with varied drug responses (i.e., responders vs. non-responders; slow or fast metabolizers). The PMx efforts could simultaneously provide information related to an individual’s pharmacokinetic response during clinical trials and be used to predict patient response to drugs making pharmacometabolomic clinical research valuable for precision medicine. PMx biomarkers can also be discovered and validated during FDA clinical trials. Using biomarkers during medical development is described in US Law under the 21st Century Cures Act. Information on how to submit biomarkers to the FDA and their context of use is defined herein.

Current Landscape of NRF2 Biomarkers in Clinical Trials

“…The opportunity to use perhaps hundreds of analytes for assessment drug pharmacodynamics, or indeed as descriptors of human health and disease, will provide greater accuracy in unraveling the complexity of human biology. Already, metabolomic profiles obtained prior to, during, or after drug treatment are used to provide insights about the drug mechanism of action and variation of response to treatment [ 235 ].…”

Current Status of Metabolomic Biomarker Discovery: Impact of Study Design and Demographic Characteristics

“…The metabolome is directly linked to perturbations in cell metabolism caused by environmental stimuli as well as disease, thus metabolomics has been successfully used to measure phenotypic outcomes in vitro and in vivo [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][40][41][42][43][44][45][46][47][48][49]. Examples include observations of oncometabolites, such as 2-hyroxybutyrate, sarcosine, choline, succinate, lactate, fumarate, and glucose, associated with tumor growth and metastasis that may also function as biomarkers for leukemia, renal carcinoma, breast, brain, or prostate cancer [26][27][28][29][30][31][32].…”

“…Examples include observations of oncometabolites, such as 2-hyroxybutyrate, sarcosine, choline, succinate, lactate, fumarate, and glucose, associated with tumor growth and metastasis that may also function as biomarkers for leukemia, renal carcinoma, breast, brain, or prostate cancer [26][27][28][29][30][31][32]. Metabolomics may also be used to accumulate additional insights during studies of clinical pharmacology and biomarker discovery [3,4,[14][15][16], recognizing that large scale and multi-cohort studies will increase the discovery of candidate biomarkers.…”

“…These technologies harvest substantial volumes of data at multiple biological levels and sift the resulting large data sets with informatics tools including artificial intelligence (AI). This intriguing approach has accelerated biomarker discovery and routinely incorporated in preclinical study workflows, including for the search for potential novel therapeutic targets and candidate drugs [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. The capability of metabolites to illustrate varied biological processes, such as cell differentiation and maturation, insulin signaling, T-cell survival, and macrophage immune responses is reported and extensively reviewed [20,21].…”

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

“…As the metabolomics research community finds ways to overcome the current limitations of this powerful technology, this will pave the way be personalized metabolic phenotyping [87,88], which holds great promise in early diagnosis [89], informed treatment choices [90], and accurate prediction of response to therapy [91]. Of note, metabolomics data has advantages as compared to other screening methods as it directly measures drug metabolism, inflammation markers, and other everchanging indicators of the patient's disease status.…”