Integrating PGx throughout the Drug Development Process

Nelson, et al. argue for integrating more pharmacogenomic research into drug screening and the pre-approval process, with benefits for patient outcomes and drug development. Their article  “The genetics of drug efficacy: opportunities and challenges,” published this week in Nature Reviews Genetics reviews currently known associations of genetic variants with drug efficacy. In addition to using other sources, they selected genes from the list of CPIC guidelines. Clinical annotations describing the relationships and evidence for the variants that appear on their list of robust associations (Table 1 of the review), such as for the association of CYP2D6 and codeine efficacy, can be found on the PharmGKB website.

With nearly all pharmacogenetic relationships discovered post-approval, dozens of drugs currently on the market and in development are likely to benefit from clinical application of pharmacogenetics. Many relevant studies simply haven’t been done. Additionally, with genetic testing platforms becoming progressively cheaper, now at $1K for whole genome sequencing, it is possible to interrogate rare variation in addition to common variation, which until now has limited the discoveries of pharmacogenetic relationships to common variants with large effect sizes.

Even while the majority of drugs may not have clinically useful genetic predictors of efficacy, Nelson, et al. have calculated that somewhere between 2 and 20% of drugs likely do, with important implications for clinical outcomes. We would like to add that beyond their statistic for drug efficacy, genetic variation can have important implications for drug safety, including risk of toxicity and hypersensitivity reactions. By integrating pharmacogenetic research earlier and more comprehensively into the drug development process, the benefit of personalized medicine related to efficacy AND safety can achieved more quickly and more completely, with additional benefits for understanding the biological mechanism of drug activity and targeted development of future drugs.