Editorial

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Open AccessEditorial

Preface to Special Issue on ‘Cytochrome P450 Variation in Pharmacogenomics’

by Allan E. Rettie and Stephen B. Liggett

J. Pers. Med. 2018, 8(3), 23; https://doi.org/10.3390/jpm8030023 - 04 Jul 2018

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(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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Research

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Open AccessFeature PaperArticle

Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

by Ida Aka, Christiana J. Bernal, Robert Carroll, Angela Maxwell-Horn, Kazeem A. Oshikoya and Sara L. Van Driest

J. Pers. Med. 2017, 7(4), 14; https://doi.org/10.3390/jpm7040014 - 02 Nov 2017

Cited by 29 | Viewed by 10784

Abstract

Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In [...] Read more.

Cytochrome P450 (CYP) enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC) data and surveyed 10 years of electronic health records (EHR) data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone). For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole). For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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Review

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9 pages, 697 KiB

Open AccessFeature PaperReview

Warfarin: The End or the End of One Size Fits All Therapy?

by Munir Pirmohamed

J. Pers. Med. 2018, 8(3), 22; https://doi.org/10.3390/jpm8030022 - 28 Jun 2018

Cited by 26 | Viewed by 8476

Abstract

Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists (of which warfarin is the most widely used and is used as the exemplar in [...] Read more.

Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists (of which warfarin is the most widely used and is used as the exemplar in this paper), and direct oral anticoagulants (DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban). This paper explores the recent advances and controversies in oral anticoagulation. While some commentators may favour a complete switchover to DOACs, this paper argues that warfarin still has a place in therapy, and a stratified approach that enables the correct choice of both drug and dose would improve both patient outcomes and affordability. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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Open AccessFeature PaperReview

Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

by Andrea Gaedigk, Jean C. Dinh, Hyunyoung Jeong, Bhagwat Prasad and J. Steven Leeder

J. Pers. Med. 2018, 8(2), 15; https://doi.org/10.3390/jpm8020015 - 17 Apr 2018

Cited by 100 | Viewed by 11889

Abstract

The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex CYP2D6 diplotype data [...] Read more.

The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex CYP2D6 diplotype data into a patient’s phenotype to guide drug therapy and is at the core of all CYP2D6 gene/drug pair guidelines issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The AS, however, only explains a portion of the variability observed among individuals and ethnicities. In this review, we provide an overview of sources in addition to CYP2D6 genotype that contribute to the variability in CYP2D6-mediated drug metabolism and discuss other factors, genetic and non-genetic, that likely contribute to the observed variability in CYP2D6 enzymatic activity. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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33 pages, 6143 KiB

Open AccessFeature PaperReview

P450 Pharmacogenetics in Indigenous North American Populations

by Lindsay M. Henderson, Katrina G. Claw, Erica L. Woodahl, Renee F. Robinson, Bert B. Boyer, Wylie Burke and Kenneth E. Thummel

J. Pers. Med. 2018, 8(1), 9; https://doi.org/10.3390/jpm8010009 - 01 Feb 2018

Cited by 22 | Viewed by 11103

Abstract

Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without [...] Read more.

Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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31 pages, 2646 KiB

Open AccessFeature PaperReview

Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine

by Sherry-Ann Brown and Naveen Pereira

J. Pers. Med. 2018, 8(1), 8; https://doi.org/10.3390/jpm8010008 - 30 Jan 2018

Cited by 68 | Viewed by 20602

Abstract

Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. [...] Read more.

Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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Open AccessReview

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations

by Ann K. Daly, Allan E. Rettie, Douglas M. Fowler and John O. Miners

J. Pers. Med. 2018, 8(1), 1; https://doi.org/10.3390/jpm8010001 - 28 Dec 2017

Cited by 130 | Viewed by 16061

Abstract

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several [...] Read more.

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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654 KiB

Open AccessFeature PaperReview

Pharmacogenomics Guided-Personalization of Warfarin and Tamoxifen

by Theodore J. Wigle, Laura E. Jansen, Wendy A. Teft and Richard B. Kim

J. Pers. Med. 2017, 7(4), 20; https://doi.org/10.3390/jpm7040020 - 13 Dec 2017

Cited by 12 | Viewed by 9661

Abstract

The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date [...] Read more.

The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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Variation in CYP2A6 Activity and Personalized Medicine

by Julie-Anne Tanner and Rachel F. Tyndale

J. Pers. Med. 2017, 7(4), 18; https://doi.org/10.3390/jpm7040018 - 01 Dec 2017

Cited by 98 | Viewed by 14969

Abstract

The cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several clinically relevant substrates, including nicotine—the primary psychoactive component in cigarette smoke. The gene that encodes the CYP2A6 enzyme is highly polymorphic, resulting in extensive interindividual variation in CYP2A6 enzyme activity and the rate of metabolism [...] Read more.

The cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several clinically relevant substrates, including nicotine—the primary psychoactive component in cigarette smoke. The gene that encodes the CYP2A6 enzyme is highly polymorphic, resulting in extensive interindividual variation in CYP2A6 enzyme activity and the rate of metabolism of nicotine and other CYP2A6 substrates including cotinine, tegafur, letrozole, efavirenz, valproic acid, pilocarpine, artemisinin, artesunate, SM-12502, caffeine, and tyrosol. CYP2A6 expression and activity are also impacted by non-genetic factors, including induction or inhibition by pharmacological, endogenous, and dietary substances, as well as age-related changes, or interactions with other hepatic enzymes, co-enzymes, and co-factors. As variation in CYP2A6 activity is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics, CYP2A6 expression and enzyme activity is an important clinical consideration. This review will discuss sources of variation in CYP2A6 enzyme activity, with a focus on the impact of CYP2A6 genetic variation on metabolism of the CYP2A6 substrates. Full article

(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)

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