Preemptive Pharmacogenomic Testing for Precision Medicine

Ji, Yuan; Skierka, Jennifer M.; Blommel, Joseph H.; Moore, Brenda E.; VanCuyk, Douglas L.; Bruflat, Jamie K.; Peterson, Larry J.; Veldhuizen, Tamra L.; Fadra, Numrah; Peterson, Sandra E.; Lagerstedt, Susan A.; Train, Laura J.; Baudhuin, Linnea M.; Klee, Eric W.; Ferber, Matthew J.; Bielinski, Suzette J.; Caraballo, Pedro J.; Weinshilboum, Richard M.; Black, John L.

doi:10.1016/j.jmoldx.2016.01.003

Cited by 168 publications

(114 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The method used to predict drug metabolizer phenotype for CYP2D6 included intermediate phenotype categories (EM to UM, IM to EM and PM to IM) according to a recent paper and was summarized in S1 Fig. [23]. …”

Section: Methodsmentioning

confidence: 99%

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

et al. 2017

View full text Add to dashboard Cite

BackgroundGenetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories.MethodsWe designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow.ResultsWe found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population.ConclusionGenotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.

show abstract

Section: Methodsmentioning

confidence: 99%

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Following on from this, in a very recent publication revealed that in this RIGHT cohort of 1,013 subjects, tested for five well-characterized pharmacogenomic genes (CYP2D6, CYP2C19, SLCO1B1, CYP2C9, and VKORC1), 99% of the participants carried a pharmacogenomics variant that could impact on the metabolism, effectiveness and sideeffect profile of a given drug [37,38]. It will be very interesting to see how a longitudinal follow up from this "RIGHT" initiative will impact on the appropriate prescribing of therapeutics.…”

Section: Pharmacogenomics and Polypharmacymentioning

confidence: 96%

“…The prediction model included age, sex, race, and 6 chronic diseases categorised by the Clinical Classifications Software for International Classification of Diseases, Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). Pre-emptive pharmacogenomic testing of this group included CYP2D6 genotyping and targeted sequencing of 84 pharmacogenomes that had FDA warnings for drug interactions.The genomic results were entered into the individuals' electronic medical record (EMR) and if a drug was prescribed for the individual potential patient-specific, drug-gene interactions would be flagged.Following on from this, in a very recent publication revealed that in this RIGHT cohort of 1,013 subjects, tested for five well-characterized pharmacogenomic genes (CYP2D6, CYP2C19, SLCO1B1, CYP2C9, and VKORC1), 99% of the participants carried a pharmacogenomics variant that could impact on the metabolism, effectiveness and sideeffect profile of a given drug [37,38]. It will be very interesting to see how a longitudinal follow up from this "RIGHT" initiative will impact on the appropriate prescribing of therapeutics.…”

mentioning

confidence: 96%

Pharmacogenomics: The Scientific Basis of Rational Drug Development and Prescribing

Abraham¹,

Jethwa²

2017

Clin Pharmacol Biopharm

View full text Add to dashboard Cite

Abstract"It is more important to know what sort of a patient has a disease than what sort of a disease a patient has" (Hippocrates 460 BC-370 BC).The holy grail of drug discovery is to ensure that an individual responds positively to an investigational drug with minimal or no adverse events. This could then translate to newly discovered drugs being licenced for prescribing as safe and effective therapeutics. Pharmacogenomics may herald the technology for this aspiration to become reality.Uniting the disciplines of pharmacology and genomics, pharmacogenomics provides a mechanism to understand and predict the response of an individual to a drug or group of drugs. This is based on the premise that an individual's genotype affects the pharmacokinetics, pharmacodynamics and, ultimately, the individual's their response to a drug. This review will begin by reviewing the history of drug development and then proceed to discuss the use of pharmacogenomics in drug development through case studies in oncology, respiratory and vaccinology. It will then go on to discuss how pharmacogenomics presently influences prescribing practices and how this technology may have the potential to enhance patient safety when medicines are administered. KeywordsPharmacology; Genomics; Pharmacokinetics; Pharmacodynamics Historical Perspective of Drug Development and PharmacogenomicsThe observation that individuals react differently to exogenous agents dates back to Ancient Greece 510 BC, where Pythagorus observed the differential effects of Fava bean consumption on individuals [1]. It was, however, not until 1956 that glucose-6-phosphate enzyme deficiency was recognised as the culprit for "Favism" and, additionally, the sensitivity to drugs such as primaquine [2]. Also in the 1950s, a German physician, Friedrich Vogel, first coined the term "pharmacogenetics". This initially concentrated on explaining the unexpected response to drugs related in relation to an individual's genetic makeup, (which usually relates to metabolism) and explored the genetic variation in a population or variations specific to a disease. It applies genomic technologies to help develop new therapeutics and potentially categorise existing therapeutics [3]. Thereafter, the completion and publication of the human genome opened the possibilities for a new era of drug discovery and personalised prescribing [4,5]. Pharmacogemonic Approaches to Drug Development and Clinical TrialsThe human genome consists of approximately 3.3 billion base-pairs and the difference between any two individuals in terms of DNA sequence is just 0.1%; it is this difference that influences disease susceptibility, progression of disease and response to drug intervention [6,7]. A solid platform for a rationalised drug discovery programme emerged with the completion of the human genome project and rapidly advancing technology.The pharmaceutical industry applies the principles of pharmacogenomics in the drug discovery programmes they oversee; it also undertakes in-depth evaluation of target gene sequences...

show abstract

“…For example, among those original 1013 subjects, if only five “common” pharmacogenes out of the 84 sequenced were included, 99.1% of the subjects had at least one actionable variant in at least one of those five genes—with many subjects having clinically actionable variant sequences in several of the five genes. 31 This observation explains why, at the beginning of this overview, we made the statement that “pharmacogenomics is the aspect of clinical genomics that will almost certainly see the earliest and broadest clinical implementation—with the potential to eventually touch the care of every patient everywhere”. To follow up on those initial RIGHT study results, the Mayo Clinic Center for Individualized Medicine, in collaboration with the Baylor Human Genome Sequencing Center, is currently moving beyond the original 1013 biobank samples to consent and sequence 10,000 additional Mayo Biobank participants for a “RIGHT 10K” study designed to test the hypothesis that having preemptive pharmacogenomic information in the EHR might result in cost-effective health benefits for the patients involved—helping them to avoid adverse drug reactions and obtain maximum efficacy from drug therapy.…”

Section: Pharmacogenomics: Clinical Implementationmentioning

confidence: 99%

Pharmacogenomics: Precision Medicine and Drug Response

Weinshilboum

Wang

2017

Mayo Clinic Proceedings

Self Cite

185

115

View full text Add to dashboard Cite

Pharmacogenomics is the use of genomic and other “omic” information to individualize drug selection and drug use in order to avoid adverse drug reactions and to maximize drug efficacy. The science underlying pharmacogenomics has evolved rapidly over the 50 years since it was first suggested that genetics might influence drug response phenotypes. That process has occurred in parallel with advances in DNA sequencing and other molecular technologies, with striking increases in our understanding of the human genome. There are now many validated examples of the clinical utility of pharmacogenomics, and this type of clinical genomic information is increasingly being generated in clinical laboratories, incorporated into electronic health records (EHRs) and used to “tailor” or individualize drug therapy. This review will survey the origins and development of pharmacogenomics; it will address some of the challenges associated with the clinical implementation of pharmacogenomics; and it will attempt to foresee future advances in this important genomic discipline, one that almost certainly will be among the earliest and most widely adopted aspects of clinical genomics.

show abstract

Preemptive Pharmacogenomic Testing for Precision Medicine

Cited by 168 publications

References 11 publications

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation

Pharmacogenomics: The Scientific Basis of Rational Drug Development and Prescribing

Pharmacogenomics: Precision Medicine and Drug Response

Contact Info

Product

Resources

About