Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice

Abstract

Interindividual variability in drug efficacy and toxicity is a major challenge in clinical practice. Variations in drug pharmacokinetics (PKs) and pharmacodynamics (PDs) can be, in part, explained by polymorphic variants in genes encoding drug metabolizing enzymes and transporters (absorption, distribution, metabolism, and excretion) or in genes encoding drug receptors. Pharmacogenomics (PGx) has allowed the identification of predictive biomarkers of drug PKs and PDs and the current knowledge of genome-disease and genome-drug interactions offers the opportunity to optimize tailored drug therapy. High-throughput PGx genotyping, from targeted to more comprehensive strategies, allows the identification of PK/PD genotypes to be developed as clinical predictive biomarkers. However, a biomarker needs a robust process of validation followed by clinical-grade assay development and must comply to stringent regulatory guidelines. We here discuss the methodological challenges and the emerging technological tools in PGx biomarker discovery and validation, at the crossroad among molecular genetics, bioinformatics, and clinical medicine.

Figure 1

Pharmacogenomic (PGx) biomarker discovery and validation process. The workflow from biomarker discovery to assay for clinical use (companion diagnostic, CDx) starts from different individual DNA sources for identification of genomic variations, high‐throughput PGx genotyping strategies (targeted, Genome‐Wide or WES/WGS). Selected annotated or unknown genomic variants, after a complex process of validation and standardization, could became a predictive or prognostic biomarkers to be translated in clinical practice as validated CDx assay for tailored drug prescriptions.

Figure 2

Germline and somatic PGx biomarkers (a); Therapeutic areas of drugs with PGx information in U.S. FDA (b).