ClinPGx 2024 Registration and Abstract Submission Open

 

REGISTRATION OPEN

In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar, the Penn Institute for Biomedical Informatics will be hosting the ClinPGx 2024: Knowledge, Implementation, Education meeting on June 20th and 21st, 2024 in Philadelphia, PA. This meeting will provide educational content to cover all aspects of PGx implementation, including knowledgebases, implementation strategy, informatics, use of AI in precision medicine, clinical laboratory insights, and more.

Participants are invited to submit abstracts for the poster sessions. You must be registered for the meeting before your abstract will be accepted.

Please note breakfast & lunch will be provided all conference days.

Registration and detailed agenda

REMINDERS / DEADLINES:

March 22, 2024: Deadline for Abstract Submission. Abstract submission form link here.

April 30, 2024: Deadline for $350 Registration Fee (Starting May 1st, registration fee will be $450)

May 20, 2024: Deadline for Hotel Reservations. Click HERE for hotels offering special rates.

June 1, 2024: Deadline to register for the event.

ClinPGx Sessions at PGRN 2023 Conference and ClinGen Summer Workshops

At the upcoming PGRN 2023 annual conference in Memphis, Dr. Teri E. Klein, the principle investigator for PharmGKB, ClinGen, CPIC and PharmCAT,  will hold a town hall discussion on ClinPGx: a single integrated resource for Pharmacogenomics (PGx). Dr. Klein will discuss the challenge of the separation of pharmacogenomic resources from clinical genomic resources, and present a long-term, conceptual framework for broadly integrating the available PGx resources into a single resource, ClinPGx. 

Dr. Klein will also present at the upcoming ClinGen 2023 Summer Workshop Series on June 16 11am PT. Please come join us. We are actively seeking feedback from the PGx and genomics community on the interest and development of ClinPGx to facilitate the incorporation of PGx into standard of care. Zoom link below: 

June 16th, 2023, 11am PT/ 2pm ET 

Join Zoom Meeting : 

https://acmg.zoom.us/j/87027015818?pwd=S2U2OTFhQ1oranFZZjNlTEhHN0FlUT09 

Meeting ID: 870 2701 5818 

Passcode: 83854960 

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+16699006833,,87027015818# US (San Jose) 

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Registration opens for CPIC-PGRN 2022 meeting in Denver, Colorado

We are excited to announce that registration is open for the 2022 CPIC-PGRN meeting: Diversifying PGx Science to Improve Implementation. The meeting will be held at the University of Colorado on May 10^th, 11^th, and 12^th in Denver, CO. Registration, agenda, and hotel information available at the meeting website. Early bird registration is now open and is $250.00.  The deadline for early bird registration is April 1, 2022. Regular registration will open April 2, 2022 and is $350.00.  The deadline to register is May 1, 2022. 

We are keeping an eye on the COVID status and will abide by the restrictions and guidelines set by the University of Colorado at the time of the meeting. We are planning a COVID “rain date” in case we need to reschedule the meeting. If the meeting is cancelled due to COVID, registration fees will be refunded. No virtual option will be available.

 

The draft agenda can be found on the meeting website. We are still finalizing final titles and speakers and we will post the final agenda once complete.

 

Participants are invited to submit abstracts for the poster sessions.  Please send your abstract to CPIC-PGRN2022@pgrn.org. Acceptance notifications and guidelines will be sent prior to the early registration deadline (April 1^st). 

 

Abstract Submission guidelines:

Final Submission Deadline: March 18th, 2022 

Required Sections:  Authors, Institutions, Background, Methods, Results, Conclusions

1 figure or table may be included

Word limit: 500 words

Please note that submitting an abstract does not register you for this meeting. 

 

Hope to see you there! If you have any questions about registration, please email kelly.caudle@stjude.org. 

 

Best wishes,

Kelly Caudle and Teri Klein (CPIC co-PIs)

Please help secure funding for PGx!!

The ability to predict ahead of time which drugs will be effective for a unique patient and determine which medications may cause patients serious issues, will save lives, improve health care outcomes, and decrease health care costs. Several genes in the human genome play a role in how people respond to medications, including how effective they will be, how quickly medication will be metabolized, and whether a person is likely to experience side effects from a particular drug. A person’s response to a medication, therefore, is impacted by the genetic variants in their those genes.

 

Pharmacogenomic testing evaluates an individual’s genetic makeup to help identify which medication and which dose is right for each patient and hopefully, prevent an adverse drug reaction. Adverse drug events (ADEs) are the most frequently cited significant cause of injury and death among hospitalized patients and can be the result of a drug-drug or drug-gene interaction. Pharmacogenomic testing can save lives by preventing ADEs. According to one estimation, there are more than 2,216,000 serious ADEs recorded in hospitalized patients every year, causing over 106,000 deaths annually, which makes ADEs the fourth leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.

 

In addition, information about drug-gene interactions is not well integrated in patient care and tools that assist with patient care, like electronic alerting systems and electronic health records. Improving pharmacogenomic education and improved record keeping would drive down health care costs. In fact, one four-month long study predicted cost-savings of $1,132 per patient using pharmacogenomic testing and an accompanying alert system as a clinical decision support tool.

 

Congressional Representatives Eric Swalwell and Tom Emmer are introducing the Right Drug Dose Now Act, a bill to improve pharmacogenomics research and patient outcomes. The bill updates the National Action Plan for Adverse Drug Event Prevention; creates a public awareness campaign for adverse drug events and pharmacogenomic testing and a separate health care professional education campaign; creates a program to improve the reporting of adverse drug events through electronic health records; and provides additional funding for NIH to improve research and reporting of adverse drug events through the Genomic Community Resources program.

Please note as part of this bill is the intent is to support with dedicated funding to PGx resources such as PharmGKB, CPIC and PharmVar.

Please reach out to Sarah Shapiro (sarah.shapiro@mail.house.gov) in Representative Swalwell’s office if you or your organization would like to support the Right Drug Dose Now Act. 

Congress needs to hear from us as community. Please help. 

Thank you in advance.  Stay Safe. Be well.

Teri

Milestones in Payer Coverage Set to Expand Pharmacogenomic Testing

 A new perspective just out in Genetics in Medicine describes the improvements in the US payer landscape for pharmacogenomics test reimbursement from this past summer and their implications for the field moving forward.

The Medicare Administrative Contractors (MACs) participating in the Molecular Diagnostic Services (MolDx) program released their final local coverage determinations (LCDs) pharmacogenomic testing in July/August.

PharmGKB and CPIC view these as significant advances because of the large number of US Medicare patients impacted. Further, the LCDs state PGx testing as reasonable and necessary when medications have a clinically actionable gene(s)-drug interaction as defined by CPIC guidelines (category A and B) or the FDA (PGx information required for safe drug administration). Coverage for panel testing was also supported if more than one gene on the panel is considered reasonable and necessary for the safe use of a medication or if multiple drugs are being considered that have different relevant gene associations. 

The authors’ analysis lists >50 gene/drug pairs that are covered by the LCD and provides a map (below) of MAC regions impacted. They make a strong argument that harmonization of coverage is needed and that standardization, improved clarity in the regulatory landscape, practitioner education, and research to measure downstream clinical outcomes are needed more than ever to fully capture the value of pharmacogenomic testing. 

Geographical impact of the new LCDs. States within MolDx jurisdictions (shaded green) as well as those that are outside of the MolDx (in other MACs) are shown.

Edit 3/3/21 - Image was updated to correct a typo

Review and Consensus on Pharmacogenomic Testing in Psychiatry published in Pharmacopsychiatry

Review and Consensus on Pharmacogenomic (PGx) Testing in Psychiatry was recently published in the journal Pharmacopsychiatry [PMID: 33147643].

In the sections pharmacogenomic mechanisms, pharmacogenomic evidence and guidelines for psychiatry, and pharmacogenomic testing in psychiatry the review provides an up-to-date summary of recent developments that clinicians should know when considering PGx testing for their patients. It summarizes and discusses the evidence that was considered by the International Society of Psychiatric Genetics (ISPG) for a statement about “Genetic testing and psychiatric disorders” updated in 2019.

The author group concludes that PGx testing should be viewed as part of the decision supporting measures to assist implementation of good clinical care, highlighting CYP2D6, CYP2C19, HLA-A, and HLA-B. For further details read the review [PMID: 33147643].

ICPC publishes GWAS analysis on platelet reactivity and cardiovascular response in patients treated with clopidogrel

The GWAS analysis on platelet reactivity and cardiovascular outcome for clopidogrel, the third paper by the International Clopidogrel Pharmacogenomics Consortium (ICPC), has just been published in journal Clinical Pharmacology & Therapeutics.

Clopidogrel is an antiplatelet agent widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Individual responses to clopidogrel show substantial variability, and poor response is often associated with adverse cardiovascular outcomes. Genetic variants in CYP2C19 play an important role in response to clopidogrel. However, loss of function variants in CYP2C19 only account for a small percentage of the overall variation in platelet reactivity, suggesting that novel genetic variants for clopidogrel response remain to be discovered.

The International Clopidogrel Pharmacogenomics Consortium (ICPC) was established to identify genetic factors influencing clopidogrel efficacy and cardiovascular outcomes, using both genome-wide and candidate gene approaches. It comprises 17 study sites from 13 countries that contributed clinical and genetic data for a total of 8,929 patients treated with clopidogrel. Investigators from ICPC performed a GWAS on data from 2,750 individuals of European ancestry. The GWAS analysis showed that CYP2C19*2 is still the strongest genetic determinant of on-clopidogrel platelet reactivity, and no SNP reached genome wide significance for major adverse cardiovascular events (MACE) endpoints. However, in subgroup analyses for patients with coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance with MACE or stent thrombosis outcomes. This study represents the largest GWAS performed to date for clopidogrel response.

In addition to the GWAS analysis, the ICPC previously published the design paper and results from the candidate gene study, which developed a pharmacogenomic polygenic response score (PgxRS) - based on 31 candidate gene polymorphisms and assessed in 3,391 clopidogrel treated patients from the ICPC.  Several variants in CYP2C19, CES1, CYP2C9, CYP2B6 and PEAR1 were identified to have significantly influenced on-clopidogrel platelet reactivity. Patients who carried increasing number of risk alleles that lead to high platelet reactivity were significantly more likely to experience adverse cardiovascular events than patients who carried alleles that lead to better platelet inhibition.

For more information, please refer to the following publications by ICPC:

1. Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC). Clin Pharmacol Ther. 2020 May 30. doi: 10.1002/cpt.1911. PMID: 32472697
2. Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur Heart J Cardiovasc Pharmacother. 2019 Sep 3:pvz045. doi:10.1093/ehjcvp/pvz045. PMID: 31504375.
3. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. PMID: 29653637

PGRN Transition

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is becoming an independent scientific society on July 1, 2020. The deadline for becoming a founding member has been extended. If you are interested in joining, please visit www.pgrn.org.

On behalf of all of the NIH PGRN funded investigators, we thank NIH for their past support, particularly our original program officer, Dr. Rochelle Long (NIGMS Director, Division of Pharmacology, Physiology and Biological Chemistry).

Update 6/29/2020 The inaugural Research In Progress (RIPS) webinar from the PGRN society will be given by Alan Shuldiner, MD, on Friday July 17 at 11am Eastern time. Dr. Shuldiner will speak on "Building bridges between industry, academia, health care systems and communities to advance Precision Medicine".

From Friday August 14, RIPS webinars will be held on the second Friday of every month at 11am Eastern time for all PGRN members. A schedule of upcoming RIPS webinars can be found here. If you are interested in joining the PGRN, you can become a member at www.pgrn.org.

Dr. Stuart Scott joins Stanford

We are pleased to announce that Dr. Stuart Scott will be joining Stanford University as a Professor in the Department of Pathology effective 1 September 2020. In addition, Dr. Scott will be Laboratory Director of the Stanford Medicine Clinical Genomics Program. Dr. Scott is moving from the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and Sema4 (previously the Mount Sinai Genetic Testing Laboratory). He is certified by the American Board of Medical Genetics and Genomics in both Clinical Molecular Genetics and Clinical Cytogenetics and Genomics. Dr. Scott’s research interests include pharmacogenomics (PGx), cytogenomics, epigenomics, and the implementation of genomic medicine. He has long standing collaborations with Stanford’s multi-institutional efforts in PGx including PharmGKB, CPIC, PharmVar and PharmCAT.

Join the new PGRN society!

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is transitioning to an independent, nonprofit scientific society, and all interested individuals are invited to sign up to become a member of the new PGRN!  The independent scientific society will continue many of the functions of the current PGRN, and we encourage you to join today to stay involved.  Benefits of joining the new PGRN include:

•         Reduced registration fees for PGRN meetings and workshops, including member receptions and poster sessions at annual meetings with large scientific societies such as ASHG and ASCPT

•         Participation in member calls/webinars and Research in Progress Seminars

•         Membership on PGRN program committees for meetings and workshops

•         Network with colleagues and establish collaborations

•         Leadership opportunities for members (e.g., serve on PGRN committees, board, and as leaders)

•         Awards for trainees and mentorship opportunities

•         Access to PGRN web pages highlighting pharmacogenomics tools and resources, events and other useful information for PGx research, education and clinical practice

Special membership rates are available for trainees, multi-year memberships, early sign ups and those from developing countries. In addition, take advantage of the opportunity to be listed on the PGRN website as a founding member if you choose that option during signup. Sign up today at https://pgrn.regfox.com/pgrn-membership-dues.

FDA releases tables on the use of pharmacogenetic testing for specific medications

CPIC and PharmGKB applaud the release of additional guidance from the FDA on the use of pharmacogenetic testing for specific medications. Numerous members of the pharmacogenetics implementation community have asked CPIC and PharmGKB for our views on the FDA release and we identify some similarities and differences below.

There are substantial areas of overlap in those gene/drug pairs that CPIC/PharmGKB and FDA consider clinically actionable. There are also a few discordances between FDA’s table and CPIC guidelines and CPIC’s classification of gene/drug pairs as level A or B (i.e. clinically actionable). For example, CPIC recommends avoiding phenytoin for phenytoin-naïve patients with HLA-B*15:02, while phenytoin is not listed yet on the FDA tables. There are also instances in which the FDA’s table states “Refer to FDA labeling for specific dosing recommendations,” but the FDA label doesn’t include specific guidance on how much to reduce dosage or provide explicit dosing recommendations (e.g. azathioprine), information which CPIC guidelines often provide.

PharmGKB clinical annotations are based on the evaluation of published literature.  CPIC guidelines are based on evidence which is referenced in detail as part of each guideline, with expert evaluation of published literature that supports (or refutes) prescribing recommendations. At this time, it is not clear what evidence has been used by FDA to construct their tables of recommendations. It would be informative to include citations to evidence supporting these FDA tables of associations for use by others in the community.

CPIC and PharmGKB are evaluating the recent tables provided by the FDA to identify the differences between these tables and the content of the PharmGKB clinical annotations, PharmGKB annotations of the labels on the FDA Biomarker table, and CPIC guidelines.  

CPIC and PharmGKB look forward to continuing to work with the FDA and the scientific community to provide evidence-based pharmacogenetic prescribing guidelines.

ACLA writes to the FDA about PGx testing

The American Clinical Laboratory Association (ACLA) has written a letter to the US Food and Drug Administration (FDA) regarding the FDA’s recent communications about pharmacogenomic (PGx) testing. The letter details the ACLA’s concerns that the FDA’s actions will have a significant impact on both patients and the field of PGx. The ACLA state their support for a legislative framework specifically for laboratory diagnostic tests (LDTs) and request a meeting with FDA leadership to discuss the matter further. You can read the full letter at the ACLA website.

Similarly, the Association of Molecular Pathology (AMP) has released a position statement on PGx testing, discussing the role of PGx in the precision medicine era and the standards which AMP believes that PGx tests should be held to. The full statement can be accessed at the AMP website.

Pharmacogenomics on Nightly News with Lester Holt

The Wednesday, June 28th edition of the Nightly News with Lester Holt featured a short segment on pharmacogenomics.

The piece briefly covered the Mayo Clinic's work in expanding the use of pharmacogenomics in the clinic. Dr. Richard Weinshilboum, co-director of the pharmacogenomics program at the Mayo Clinic, was also interviewed. Dr. Weinshilboum is a leader in the field, and has been a co-author on a number of PharmGKB publications, including multiple PharmGKB pathways and VIPs, as well as the International SSRI Pharmacogenomics Consortium (ISPC) publication. He is also a member of the Pharmacogenomics Research Network (PGRN); PharmGKB is a partner of the PGRN.

PharmGKB provides a page for clinically relevant pharmacogenomic summaries - a list of clinical annotations that contain variant-drug combinations featured in a guideline published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) or other medical society, or implemented at a PGRN site or a major health system, such as the Mayo Clinic. This includes associations such as codeine and CYP2D6 or thiopurine drugs and TPMT; both of these associations have CPIC guidelines. The page also features variant-drug combinations that have a preponderance of evidence showing an association, and therefore may be clinically actionable, but are not currently featured in a guideline.

CPIC Meeting at ASCPT on March 15, 2017

The Clinical Pharmacogenetics Implementation Consortium(CPIC®)  Meeting will be held on March 15, 2017, in conjunction with the 2017 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) on March 15-18, 2017 (Washington, DC).

The one-day symposium is organized by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) (cpicpgx.org) as part of the Pharmacogenomics Research Network (PGRN) (www.pgrn.org).   The CPIC-PGRN Meeting is open to all and features presentations from a world-class group of speakers who will describe current examples of implementation of pharmacogenomics in the clinic. There will also be panel discussions to summarize topics and encourage audience participation. Presentations will include “best cases” as well as challenging cases for implementation, and will include international perspectives on clinical use of pharmacogenomics.  More details can be found at https://cpicpgx.org/meetings/

CPIC® is one of the enabling resources funded by the National Institutes of Health as part of the PGRN, and is a shared project between PharmGKB (www.pharmgkb.org) and the PGRN.  The mission of the PGRN is to catalyze and lead research in precision medicine for the discovery and translation of genomic variation influencing therapeutic and adverse drug effects. CPIC’s goal is to facilitate translation by overcoming some of the barriers to implementation of pharmacogenetic tests into clinical practice. Over 150 CPIC members from 19 countries participate to developing tools to facilitate clinical implementation of pharmacogenetics, primarily by developing freely available, peer-reviewed, updatable, and detailed gene/drug clinical practice guidelines.

PGRN meeting at ASHG October 17-18, 2016

The PGRN is hosting a symposium, The Expanding Universe of Pharmacogenomics, right before the ASHG Annual Meeting in Vancouver, Canada on October 17 & 18, 2016.  The symposium is open to all ASHG attendees, PGRN members and others who are interested.

Details and agenda can be found at http://www.pgrn.org/ashg-2016.html.

Pharmacogenomics Clinical Annotation Tool (PharmCAT)

An active area of genomic medicine implementation at many health care organizations and academic medical centers includes development of decision support and return of results around pharmacogenomics.  The Clinical Pharmacogenetics Implementation Consortium (CPIC) has established guidelines surrounding gene-drug pairs that can and should lead to treatment modifications based on genetic variants.  One of the challenges in implementing pharmacogenomics is the representation of the information in the CPIC guidelines (including star-alleles) and extracting these variants and haplotypes from genetic datasets.  In a collaboration between the PGRN Statistical Analysis Resource (P-STAR), the Pharmacogenomics Knowledgebase (PharmGKB), the Clinical Genome Resource (ClinGen), and CPIC, we are developing a software tool to extract all CPIC guideline gene variants from a genetic dataset (represented as a vcf), interpret the variant alleles, and generate a report.  The CPIC pipeline report can then be used to make future treatment decisions. 

We assembled a focus group of thought leaders in pharmacogenomics to brainstorm and design the software pipeline.  We hosted a one-week Hackathon at the PharmGKB at Stanford University to bring together computer programmers with scientific curators to implement version one of this tool.  We will host a meeting to summarize and evaluate next steps in mid-May including the development of a manuscript and dissemination plan for the tool.  This software pipeline will be made available in a Creative Commons license and disseminated in GitHub later this spring for all in the scientific community to test, explore, improve and to give us feedback.  Be a part of this project!  As many of our institutions are building implementation workflows for pharmacogenomics, our ability to automate some of the extraction of genes/variants of interest would be enormously helpful.

We welcome scientific input from our colleagues.  If you would like to become involved in this effort, we ask that you contact pharmcat@pharmgkb.org.  Thank you!

A Study of the Transcriptomic Variation Affecting Pharmacogenes

In an effort to capture differences in the expression of pharmacogenes between individuals and between tissue types and to characterize novel pharmacogene splice variants, researchers conducted a transcriptomic analysis of 389 pharmacologically important genes in liver, kidney (cortex), heart (left ventricle), and adipose tissue from 139 individuals as well as 45 lymphoblastoid cell lines (LCLs). Tissue samples came from various Pharmacogenomics Reseach Network (PGRN) groups. The list of pharmacogenes was compiled from several sources, including PharmGKB. The results were recently published in The Pharmacogenomics Journal.

The study, “Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines”, reports that many pharmacogenes were highly expressed in liver or kidney when compared to other tissues, although some were consistently expressed at high or low levels in all tissue types, and that many pharmacogenes showed variable expressed when comparing between individuals and tissue types. The authors suspect that some differences in expression between individuals may reflect environmental and health differences between people. Expression of most pharmacogenes was almost always lower in LCLs when compared to the other tissue types that were examined. Finally, the authors report the discovery of several novel pharmacogene splicing events and splice variant differences between tissue types.

These findings suggest that variable expression of pharmacogenes between tissue types and individuals as well as differences in alternative splicing patterns could contribute to the observed variation in drug dosing, response, and toxicities.

The PGRN Translational Pharmacogenetics Program (TPP) publishes paper on overcoming challenges of real-world implementation

The Translational Pharmacogenetics Program (TPP) is a Pharmacogenomics Research Network (PGRN)-led initiative with the goal to identify barriers and develop real-world solutions to implement evidence-based pharmacogenetic tests in diverse health care settings. The participating sites include 6 implementation institutions (Universityof Maryland, University of Florida, St. Jude Children's Research Hospital, Vanderbilt University, Mayo Clinic, and Ohio State University),  as well as PharmGKB which serves a coordination and knowledge sharing and dissemination role and  Pharmacogenomic Ontology (PHONT) at the Mayo Clinic which provides data harmonization and standardization support.

The TPP investigators has published the design manuscript in Clin Pharmacol Ther this month. This paper discusses challenges and implementation barriers to translation of pharmacogenomics in clinical practice. Each implementation site institutes CLIA-based pharmacogenomics testing, reports results in EHR for clinical decision and tracks summary descriptions and implementation metrics to objectively evaluate the effectiveness of implementation. TPP also creates "look up" tables (posted on PharmGKB) which contain phenotype and clinical decision support system information based on haplotypes and diplotypes. These tables “complement the existing CPIC guidelines by providing therapy recommendations for a more comprehensive coverage of pharmacogenetic test results. They represent the current state of knowledge and demonstrate the range of observed results and recommended actions across sites”.

Read more:

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-World Implementation.

Shuldiner AR, Relling MV, Peterson JF, Hicks K, Freimuth RR, Sadee W, Pereira NL, Roden DM, Johnson JA, Klein TE. Clin Pharmacol Ther. 2013 Mar 19. doi: 10.1038/clpt.2013.59.