Implementation of pharmacogenomics: Where are we now?

Abstract

Pharmacogenomics (PGx), examining the effect of genetic variation on interpatient variation in drug disposition and response, has been widely studied for several decades. However, as cost, as well as turnaround time associated with PGx testing, has significantly improved, the use of PGx in the clinical setting has been gaining momentum. Nevertheless, challenges have emerged in the broader clinical implementation of PGx. In this review, we will outline current models of PGx delivery and methodologies of evaluation, and discuss clinically relevant PGx tests and associated medications. Additionally, we will describe our approach for the broad implementation of pre‐emptive DPYD genotyping in patients taking fluoropyrimidines in Ontario, Canada, as an example of clinically actionable PGx testing with sufficient clinical evidence of patient benefit that can become a new standard of patient care. We will highlight challenges associated with PGx testing, including a lack of diversity in PGx studies as well as general limitations that impact the broad adoption of PGx testing. Lastly, we examine the future of PGx, discussing new clinical targets, methodologies and analysis approaches.

Predicted deleterious variants in the human genome relevant to gene therapy with adeno-associated virus vectors

“… 35 Efficacy to approved drugs varies from 25% to 80%, 35 with increasing evidence that genetic variation plays a role in the efficacy of a given drug in each individual. 35 , 36 , 37 In the present study, the analysis of genes shown to play a role in AAV-mediated gene transfer and expression demonstrates that this may also be the case for AAV gene therapy. Like other drugs, AAV gene therapies have been associated with variable responses despite administration by the same route and dose adjusted to the physical characteristics of the recipient.…”

Pharmacogenomics in practice: a review and implementation guide

“…Establishing or updating well-defined regulations will ultimately force insurance companies to revise their coverage plans to enable PGx testing. A success story is the experience of genotyping for DPYD variant alleles upon fluoropyrimidines prescribing whereby the resulting clinical and economic benefits led to securing governmental financial support in Ontario, with further evidence of cost-effectiveness probably leading to expansion of the experience to other medical institutions ( Brooks et al, 2022 ; Medwid and Kim, 2022 ; Varughese et al, 2022 ). Moreover, the EMA recommended testing for DPYD, but concerns regarding the economic benefit and cost-effectiveness of testing resulted in slow adoption of the recommendation.…”

“…Consequently, a list of drugs was suggested by several investigators as ready to be implemented. This list includes but is not limited to: statins, clopidogrel, and warfarin for cardiovascular diseases, codeine and tramadol as opioid analgesics, ondansetron and proton pump inhibitors for gastrointestinal illnesses, fluoropyrimidines, tamoxifen, and thiopurines for cancer, and antidepressants such as the selective serotonin reuptake inhibitors ( Weitzel et al, 2019 ; Rollinson et al, 2020 ; Medwid and Kim, 2022 ). Finally, a fourth study evaluated the longitudinal exposure in primary care in the United Kingdom of a list of 63 drugs identified from the PharmGKB database to be associated with 19 pharmacogenes.…”

“…This list is non-exhaustive and laid out for illustrative purposes only. It is based on the most commonly proposed variants and genes in the literature ( Samwald et al, 2016 ; van der Wouden et al, 2017 ; Chanfreau-Coffinier et al, 2019 ; van der Wouden et al, 2019 ; Rollinson et al, 2020 ; Medwid and Kim, 2022 ) and supported with high quality evidence, clinical guidelines and/or drug labels with genetic information. We also chose variants that are relatively common in Africans, Asians or Europeans.…”

A Genetic Analysis of Current Medication Use in the UK Biobank

“…Fundamental to the development of genomic medicine is accurate knowledge regarding the disease pathogenesis and acknowledging the genetic contributions to variation in how patients respond to treatment [ 7 ]. Genetic variation among patients modulates drug efficiency and can impose toxic effects (adverse drug reactions) [ 8 ]; thus, understanding how genetic variation affects drug response is essential for the development of genomic medicine.…”