Monday, October 2, 2017

10 New Pharmacokinetics Pathways on PharmGKB

PharmGKB releases ten new PK pathways on the website:

Antipsychotics: Clozapine, Haloperidol and Olanzapine
Antiepileptic: Clobazam
NSAIs: Naproxen
Anti-cancer drug: Dasatinib
Anti-hypertensive drug: Verapamil
         

If you are interested in collaborating to develop these for publication as a PharmGKB summary in Pharmacogenetics and Genomics journal please email feedback@pharmgkb.org


Thursday, September 28, 2017

Curators' Favorite Papers

For this month's edition of "Curators' Favorite Papers" we present two articles discussing how the recommendations from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines have been used at two different healthcare settings.

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services by Sissung et al. discusses the experience of the Cleveland Clinic with pharmacogenetic (PGx) implementation as well as how a collaboration between pharmacists and physician-geneticists established an ambulatory PGx clinic to provide testing, interpretation, prescribing recommendations, and patient education. The authors go on to discuss how the implementation of three CPIC guidelines (HLA-B*57:01 and abacavir and HLA-B*15:02 and carbamazepine and TPMT and thiopurines) was managed by pharmacists that incorporated patient data into electronic health records (EHR) who developed clinical decision support tools (CDS) based on CPIC guidelines and included custom pre- and post-test alerts. The selection of which guidelines to implement was based on third-party payment reimbursement for genetic tests, the life-threatening nature of potential adverse events as recognized by the Food and Drug Administration (FDA) in drug labels and physician support.

Pharmacogenomics Implementation at the National Institutes of Health Clinical Center also by Sissung et al. reviews the PGx implementation process at the National Institutes of Health Clinical Center (NIH CC), which uses the recommendations of CPIC guidelines to inform the selection of gene-drug pairs to be implemented.  The NIH CC has already implemented PGx testing and prescribing recommendations for HLA-B alleles with allopurinolabacavir, and carbamazepine, and it is currently in the process of PGx implementation for genes involved in the absorption, distribution, metabolism, or excretion (ADME) of drugs using the DMET genotyping platform.  The NIH CC model makes PGx testing, results and recommendations available to all NIH clinicians and also makes test results available to patients and their personal care physicians. The NIH CC expects to cover all CPIC gene-drug pairs within the next five years.


Additional guidelines can be found on the CPIC and PharmGKB and additional information about drugs and genes can also be found on PharmGKB.

Wednesday, September 27, 2017

Genotype-Guided Warfarin Dosing Lowers Rate of Composite Adverse Events vs. Clinical Dosing

Warfarin is a widely prescribed blood-thinning agent to prevent strokes, heart attacks, and blood blots. Despite the extensive literature documenting the significant association between CYP2C9/VKORC1 genotypes and warfarin dose, there's still debate surrounding the clinical utility of the genotype-guided warfarin dosing. A few large randomized clinical trials have been published with mixed results. Using the percentage of time that a patient is within the therapeutic range (PTTR) as the primary endpoint, two studies (Kimmel et al 2013, Verhoef et al 2013) showed no significant difference between the genotype-guided group vs. control, while one study (Pirmohamed et al 2013) suggested improvement with added genetic information. Additionally, these trials were not powered to examine clinical outcomes such as bleeding and thrombotic complications. The long-awaited Genetic Informatics Trial (GIFT) of warfarin is the first warfarin pharmacogenetics trial powered for these safety outcomes. The result of GIFT trial has just been published this month in JAMA and demonstrated genotype-guided warfarin dosing lowered the combined risk of adverse events compared to clinical dosing.

In this multicenter randomized controlled trial, 1650 patients 65 years or older initiating warfarin for elective hip or knee arthroplasty were randomized to receive either genotype-guided or clinically-guided warfarin dosing on day 1 through day 11 of therapy. 1597 patients completed the trial. The primary endpoint was the composite of major bleeding, venous thromboembolism, international normalized ratio (INR) of 4 or greater, and death. The GIFT trial included genotyping for CYP2C9*2, *3, VKORC1 -1639G>A and CYP4F2 V433M, but did not include the African American specific CYP2C9 alleles or CYP2C variant rs12777823 (6.4% of the 1597 patients were black). The rate of composite adverse events was 10.8% in the genotype-guided group, versus 14.7% in the clinically guided group, corresponding to 3.9% absolute risk reduction ([95%CI, 0.7%-7.2%], p=0.02) and 27% relative risk reduction (RR=0.73, [95% CI, 0.56-0.95]). The absolute reduction in risk appears to be primarily due to improved INR control in the genotype-guided group. This is the first randomized controlled trial confirming the clinical benefit of genotype-guided warfarin dosing with a lower rate of adverse events, exemplifying the use of genetic information to improve patient outcomes.

Read the articles:

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty The GIFT Randomized Clinical TrialJAMA. 2017;318(12):1115–1124. 
Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodríguez T, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Dávila-Román V, Eby CS

Editorial:
Pharmacogenomic Testing and Warfarin What Evidence Has the GIFT Trial Provided?JAMA.2017;318(12):1110–1112
Emery JD

More information on warfarin dosing:

CPIC Guideline for Pharmacogenetics-Guided Warfarin Dosing



Tuesday, September 26, 2017

PharmVar Launches Website

The Cytochrome P450 (CYP) Allele Nomenclature Database has transitioned to the Pharmacogene Variation Consortium at www.PharmVar.org.  Please check out the PharmVar website!

Monday, September 4, 2017

Welcome to the new PharmGKB website!

We have just launched our new and improved user interface for PharmGKB!

The new website offers benefits such as a display that works on mobile and small screen devices, improved searching and filtering capabilities and faster page load speeds.  While the look of PharmGKB has changed, all the content that was available previously is still available.  More information about the new site can be found by following the online tutorial at the prompts.

We hope you like the new look and functionality.  There may be some tweaks to the site over the next few weeks as everything is optimized.  If you notice any problems or have any feedback, please click the "envelope" icon on the bottom right corner of the screen to send us feedback.  Please remember to include your email address if you would like a response!


Friday, August 25, 2017

Announcing PharmVar


PharmVar will be taking over the allele designations for the cytochrome P450 genes from the Human Cytochrome P450 (CYP) Allele Nomenclature Database, and later expanding to become a central repository for other pharmacogenes as well.  PharmGKB will partner with PharmVar to make sure PharmGKB has the most up-to-date pharmacogene allele information available in PharmVar.



Tuesday, August 8, 2017

Pharmacogenetics/Genomics (PGx) and Depression Featured on NBC News

On August 7th, NBC News aired a segment on how pharmacogenomics can help treat patients with depression. It highlighted the story of Sarah Ellis from Sioux Falls, SD who had trouble finding a combination of antidepressant and anti-anxiety medications that did not induce debilitating adverse effects. She had tried 23 different combinations of antidepressants over the course of several years until her psychiatrist intuited that pharmacogenetic (PGx) testing might help her. When her test results showed that she did carry genetic variants that affected her response to specific classes of medications, her psychiatrist prescribed an alternative class of medications and altered her dose - thereby personalizing her medications to her genetics. According to Sarah Ellis: “My energy's been really great," she says. "I feel like I can accomplish what I want to accomplish. This was definitely worth it.”

PharmGKB has been annotating these gene-drug associations since it began in 2000. Using PharmGKB, one can find drug labels annotated with pharmacogenetic information (and genetic testing recommendations if available), pathway summaries and diagrams, and clinically relevant pharmacogenetic summaries for many drugs including those used to treat depression and anxiety. PharmGKB has also contributed to research with the International SSRI Pharmacogenomics Consortium. In addition, it has contributed to the clinical implementation of PGx through the Clinical Pharmacogenetics Implementation Consortium (CPIC), which has published two guidelines (and one update) for PGx-based prescribing and dosing of two commonly prescribed classes of drugs used to treat anxiety and depression: tricyclic antidepressants (TCA) and SSRIs.