Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity

Abstract

Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

Implementation and obstacles of pharmacogenetics in clinical practice: An international survey

“…Efforts on standardization of PGx tests and their interpretation, and incorporation of CDS into EMRs should provide more common ground among heterogeneous health IT infrastructures and improve PGx integration in the clinical workflow . It is hoped that the rapid developments in next generation sequencing and machine learning lead to the further implementation of PGx in the clinic while still being practical and cost‐effective …”

“…34 It is hoped that the rapid developments in next generation sequencing and machine learning lead to the further implementation of PGx in the clinic while still being practical and cost-effective. [49][50][51][52]…”

Evaluation of Current Regulation and Guidelines of Pharmacogenomic Drug Labels: Opportunities for Improvements

“…Overall estimations have been made, identifying 20–30% of this variability to be attributable to genetic factors, although an exact figure is difficult to define . Twin studies do indicate that the genetic influence for the pharmacokinetics of certain drugs is very high . Indeed, in some cases, the genetic background for such variability still has to be identified, including the exact role of rare genetic variants …”

Development of the PGx‐Passport: A Panel of Actionable Germline Genetic Variants for Pre‐Emptive Pharmacogenetic Testing

“…Another important challenge hampering adoption of pre‐emptive panel testing is the lack of standardization regarding variants included in such panels. Additionally, recommendations on which variants to test differ strikingly across the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labels and also CPIC and DPWG recommendations . Standardization, however, would enable clinicians to understand PGx test results without extensive scrutiny of the alleles included in the panel.…”

“…Additionally, recommendations on which variants to test differ strikingly across the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labels and also CPIC and DPWG recommendations. 27 Standardization, however, would enable clinicians to understand PGx test results without extensive scrutiny of the alleles included in the panel. Despite the identification of standardization as a potential accelerator for PGx adoption, exchange, and continuity, 28 there are currently no standards defining which variants must be tested.…”