Progress and Challenges in Pharmacogenomics

Pharmacogenetics has been widely accepted as a crucial factor of interindividual variation drug response, and there is increasing information on the potential influences genetic included in summary product characteristics various drugs. Moreover, 26 current guidelines compiled by Clinical Implementation Consortium are community clinical pharmacologists. However, challenges remain to build further evidence for additional drugs diverse populations, develop feasible decision support systems, economic incentives broad implementation pharmacogenetics. Indeed, level showing significant benefit patients treated according pharmacogenomics-based compared with treatment-as-usual decisive acceptance pharmacogenomics an indispensable health care systems. It understandable that testing genes associated severe adverse events was first became mandatory before prescription (e.g., abacavir-induced hypersensitivity being strongly linked HLA-B*57:01). The attempts better understand mechanisms HLA-associated reactions, however, still ongoing. In this special issue Pharmacogenomics, Deshpande et al. summarize highly interesting insights HLA-related immunopharmacogenetics,1 novel data presented Liu HLA-loci reactions pegaspargase pediatric leukemia.2 mentioned above, it all about evidence. Most pharmacogenetic traits related variants metabolizing enzymes modulating bioavailability contrast essentially concentration independent, here, question not “yes” or “no.” most cases, dose recommendations made based genotype-predicted phenotypes. Hence, much more uncertainty true individual metabolic activity, large randomized trials could provide solid pharmacogenetics-guided therapy. review Luzum “Moving Into Practice: It’s All About Evidence!” excellently outlines sometimes variable requirements necessary implement pharmacogenetics-based into care.3 white paper from Whirl-Carrillo provides another advancement pharmacogenetics evidence, Pharmacogenomics Knowledgebase (PharmGKB) describes objective scoring system consistent, reproducible, transparent assessment variant-drug pairs.4 some areas, accumulation many association studies over years study increases confidence providers can pharmacogenetic-guided therapy avoid increase response. This case, particular, psychiatric diseases. Here, successful treatment patient’s adherence often limited due inadequate active concentrations because unknown genes, such CYP2D6 CYP2C19, and/or non-consideration drug-drug interactions potentially causing phenoconversions enzymes. their article depression, Zanardi real-world applications challenges. Aside issues testing, authors outline lack long-term follow-up integrated electronic record (EHR)5; see also integration results EHR systems Cook al.6 Similarly, antipsychotic implemented; although number confirmed strong role CYP2D6, labels have adapted available. Further promising markers involved pharmacodynamics response additionally outlined Islam al.7 Another well-established drug-gene comes high-dose simvastatin SLCO1B1, encoding hepatic uptake transporter OATP1B1. work supported Darrell Abernethy Early Stage Investigator Award ASCPT, Lu extended SLCO1B1 statin-induced myotoxicity lovastatin, presenting fourfold elevated risk rhabdomyopathy homozygote variant carriers wildtype. More needed atorvastatin.8 Wendt colleagues expand knowledge statin pharmacogenomics. Using UK Biobank, they observed slight but between haplotypes arylamine N-acetyltransferase 2 (NAT2) gene use simvastatin. pharmacological background finding remains be elucidated.9 affecting require consideration only differential binding properties given dependency at site action. effects multifactorial, and, so far, (despite HLA-markers) applied predictive biomarkers. problem elaborated Hertz mini-review “Analysis Approaches Identify Pharmacogenetic Associations With Pharmacodynamics” issue.10 Translation complex practice perfectly exemplified approaches cancer above-mentioned consequences hereditary variants, somatic mutations altered expression key drivers considered planning conductance modern therapeutic regimes. comprehensive timely pharmacogenomics-guided colon cancer, Diasio demonstrate how both well should toxicity one side elevate efficacy through targeted other side.11 extent which rare contribute overall persistent question. estimation depends largely functionality cannot fully elucidated experimental approaches. computational tools required assess functional far characterized reviewed Zhou Lauschke.12 Such methodologies particularly helpful when performing move beyond toward These may identify variety known functionality. systematic genomewide (GWASs) pharmacogenomics, McInnes subsequent fine mapping causal used diagnostic purposes, any associations must external cohorts.13 An GWAS datasets heritability genomic architecture outcomes indicated learned genome, provided requisite generated.14 Finally, pharmacokinetics partly affected traits; variability endogenous factors, organ failure regulation absorption, distribution, metabolism, excretion exogeneous like co-medication. latter phenoconversion inhibition induction therefore routinely interactions, called drug-drug-gene challenge solved far. addressed perspective Bruckmueller Cascorbi.15 Studies influence advanced investigations single (and whole genome) Our cover art month features addition pharmacogenomic toolkit pharmacology depiction Manhattan Plots representing cities highest populations tallest buildings every continent (Figure 1). As we forward, will do remember span basic translational spectrum wide array therapeutics considering diversity populations. For practice, gaps overcome reduce routine optimize therapy). Pharmacology & Therapeutics gives important field forward.