The emerging era of pharmacogenomics: current successes, future potential, and challenges

Abstract

The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.

Current perspective on pediatric pharmacogenomics

“…Some of these variations can lead to protein under-expression or a complete lack of function (like in the example of CYP2D6*4 or CYP2D6*5 alleles), whereas other rearrangements can cause an over-expression like in the case of duplicated (CYP2D6*xN) alleles. [7,8] The presence of two non-functional alleles renders the individuals poor metabolizers of CYP2D6 substrates, while having two reduced function alleles or one non-functional and one reduced activity allele make their carriers intermediate metabolizers. Moreover, extensive metabolizers are defined as the ones carrying two wild-type normal-activity alleles or one of these alleles in combination with a reduced function or a non-functional allele.…”

“…[7,8] The need for a better understanding of the codeine pathway found its roots in pharmacogenomics after fatal incidences in clinical practice in which children who were ultra CYP2D6 metabolizers (or their mothers in the case of breast-fed children) have been exposed to an excessive dose of morphine leading to subsequent severe respiratory depression. [7][8][9] Consequently, the Food and Drug Administration (FDA) communicated a black box warning against codeine use to manage postoperative pain in children and it recommends to use alternate analgesics for CYP2D6 ultra-rapid and poor metabolizers. [10] In cancer therapy, patients routinely receive multi-drug combinations.…”

“…[8,17] As a result of the growing body of evidences confirming the importance of genotyping for variants in the CYP2D6, TPMT and HLA genes as well as many others, the FDA and the Clinical Pharmacogenetics Implementation Consortium (CPIC) published guidelines to help clinicians understand the dimensions of the genetic component of treatment response variability and provide recommendations on how to use this information to guide the treatment. [1,[6][7][8]13,14] In conclusion, pharmacogenomics showed evidencebased benefits in multiple treatment areas including cardiology, neurology, oncology, pain management, organ transplantation, and immunosuppression. While genomewide association and candidate-gene studies continue to identify significant associations between genetic variants and pharmacotherapy, [18] the clinical usefulness of these findings is still unclear.…”

How to Improve the Safe and Effective Use of Doxorubicin in Children with Cancer

“…For only a few of these candidate genes (SLC28A3 and UGT1A6), this association has been replicated in independent patient groups [9]. These markers have been shown to improve risk prediction beyond established clinical risk factors [5,6].…”

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics

“…The major limitation of most evidence-based drug therapies involves making decisions based on information obtained from clinical trials, which are based on the average response to drug treatments administered at standard doses in a relatively small population with specific characteristics. As a result, at the same drug dosage, a certain group of patients may experience no therapeutic benefit, whereas others may develop severe adverse drug reactions [48,49] .…”