CPIC Guideline Update for Allopurinol and HLA-B*58:01 Published

The 2015 update of CPIC guideline for allopurinol and HLA-B*58:01 has been published in Clinical Pharmacology and Therapeutics. CPIC extensively reviewed the recent literature and concluded that the dosing recommendations provided in the 2013 CPIC guideline have not changed.

The 2015 update includes the following additions:

• Updated evidence linking HLA-B*58:01 to phenotype (Supplemental Table S3).
• Added figures depicting clinical implementation workflow for EHR and Point of Care Clinical Decision Support (Supplemental Figures S1 and S2)

View the interactive CPIC allopurinol dosing guideline based on HLA-B*58:01, with the available full update and original published guidelines.

March/April SNPits Summary

In the March/April issue of UF Health Personalized Medicine Program's e-newsletter, SNPits, a recent study in the Lancet supports the benefit of pharmacogenomic testing for warfarin dosing is reviewed.  The authors found that those patients with warfarin-sensitive genotypes were more likely to be over-anticoagulated in the first 90 days.  Additionally, there were more overt bleeding events for patients with warfarin-sensitive genotypes.  Read more.

Annotated Health Canada product monographs now available on PharmGKB

PharmGKB now has annotated drug labels (referred to as product monographs) available from Health Canada/Santé Canada (HCSC).

PDF copies of the product monographs were sourced from HCSC's Drug Product Database (DPD). As with the annotated U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceutical and Medical Devices Agency, Japan (PMDA) drug labels, HCSC monographs are given a PGx level of evidence, and a PDF copy of the product monograph with PGx information highlighted is available for each annotated monograph.

HCSC product monographs were selected for examination for PGx information based on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling, as well as any EMA labels with PGx information that PharmGKB has curated.

It is possible that there are other HCSC product monographs that contain PGx information, and PharmGKB welcomes any feedback regarding PGx information within HCSC product monographs or labels from other medicine agencies around the world.

See a list of product monographs available on PharmGKB:
HCSC product monographs on PharmGKB

NIGMS announces funding changes for PGRN

NIGMS announces the transition of pharmacogenomics research from set-aside funding to regular competition.  The FOA for Research Centers for Pharmacogenomics in Precision Medicine (P50) is discontinued for 2015 and 2016.  Starting in mid-July, any investigator interested in PGx can join the Pharmacogenomics Research Network through the PGRN website. 

PharmGKB efavirenz pharmacokinetic pathway published in Pharmacogenetics and Genomics

The PharmGKB summary describing the efavirenz (EFV) pharmacokinetic pathway, and the pharmacogenetic variants that affect EFV pharmacokinetics has been published by Pharmacogenetics & Genomics. 

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor that is used as part of a highly active anti-retroviral therapy (ART) regimen (HAART) against HIV-1 infection. The primary route of EFV metabolism is through CYP2B6 to 8-hydroxyefavirenz (8-hydroxy-EFV).  In vitro studies using human liver microsomes show that there is considerable variability in the formation rate of 8-hydroxy-EFV between samples and genetic variants in CYP2B6 are likely major contributors to this variability. There is also evidence that CYP3A4, CYP3A5, CYP1A2 and CYP2A6 also play minor roles in this xenometabolic step. 

View the interactive online version of the PharmGKB summary: Efavirenz pathway, pharmacokinetics (PK) here and on Pubmed.

View all pathways on PharmGKB. 

New CPIC Guideline: CYP2D6 and CYP2C19 and Selective Serotonin Reuptake Inhibitors

Guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) regarding the use of pharmacogenetic tests for CYP2D6 and CYP2C19 in dosing selective serotonin reuptake inhibitors (SSRIs) have been accepted for publication in Clinical Pharmacology and Therapeutics.

SSRIs are used as a first line treatment for major depressive and anxiety disorders, and may be used to treat other psychiatric conditions. Paroxetine and fluvoxamine are extensively metabolized by CYP2D6 and variations in CYP2D6 activity may result in lower or greater exposure to these drugs. While variations in CYP2C19 activity may result in altered drug exposure for citalopram, escitalopram, and sertraline.

For therapeutic recommendations and further details see these guidelines for paroxetine, fluvoxamine, citalopram, escitalopram, and sertraline on PharmGKB.

GWAS on SSRI treatment outcome in patients with depression: ISPC cohort and meta-analysis

The treatment response to selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs, varies considerably between patients. The International SSRI PharmacogenomicsConsortium (ISPC) was established with the primary goal of identifying genetic variations that may contribute to SSRI treatment outcome in patients with depressive disorder.

  The ISPC includes eight research groups that contributed clinical and genetic data. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites and the results are published in the journal Translational Psychiatry.

  Although many top association signals in the ISPC analysis for the primary outcomes percent change in HRSD-17 score and response map to interesting candidate genes (see Table 2 in the article), none were significant at the genome-wide level. The associations did not replicate using data from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. 

Top association results in the meta-analysis of response based on data from the ISPC, PGRN-AMPS and STAR*D cohorts included SNPs in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4) /VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (p=5.03E-08), and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (p=1.20E-06).