Tuesday, March 5, 2019

New CPIC Guideline: CYP2D6 and atomoxetine

The CPIC Guideline for atomoxetine and CYP2D6 is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB page for atomoxetine, and the CPIC website.

Atomoxetine is a non-stimulant medication used in the treatment of attention-deficit/hyperactivity disorder. Atomoxetine is metabolized by CYP2D6 and  genetic variation effects atomoxetine pharmacokinetics. Atomoxetine exposure is on average 10-fold higher in CYP2D6 poor metabolizers (PMs) compared to non-PMs and the likelihood of favorable treatment response and side effects are both reported to be higher in CYP2D6 PMs compared to non-PMs.

The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for atomoxetine based on CYP2D6 genotype. The therapeutic recommendation for each CYP2D6 phenotype class also includes guidance for plasma drug concentration testing.

For further details see the guidelines and supplement on CPIC, or on the pages for atomoxetine on PharmGKB.

Tuesday, December 11, 2018

New CPIC guideline: potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes

The CPIC Guidelines for potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB pages for RYR1 and CACNA1S, and the CPIC website. 

Potent volatile anesthetic agents are used for inducing general anesthesia.  Malignant hyperthermia susceptibility can lead to life-threatening reactions to these agents or the depolarizing muscle relaxant succinylcholine.
The CPIC guideline and supplement summarize evidence from the literature for 48 RYR1 and 2 CACNA1S variants identified by the European Malignant Hyperthermia Group as 'diagnostic mutations'. 

For further details see the guidelines and supplemental materials on 
CPIC, or 
the PharmGKB guideline annotation on the pages for RYR1 and CACNA1S.

Friday, December 7, 2018

CPIC Dosing Guidelines for DPYD and Fluoropyrimidines Updated

An update to the CPIC dosing guidelines for DPYD and fluoropyrimidines has recently been added to the CPIC and PharmGKB websites.

The most recent version of the guideline, published in Clinical Pharmacology & Therapeutics in November 2017, recommended that patients who were DPYD intermediate metabolizers with an activity score of 1 have a dose reduction of 50%, while those with an activity score of 1.5 have a dose reduction of 25%-50%. At the time of guideline publication, this dose range was recommended due to limited evidence for genotype-guided dosing for an activity score of 1.5.

However, a recent study in The Lancet Oncology by Henricks et al. found evidence supporting a dose reduction of 50% in individuals with an activity score of 1.5 (more on this paper can be found in a related PharmGKB blogpost). Upon consideration of this new data, CPIC revised its recommendation such that all DPYD intermediate metabolizers, both those with an activity score of 1 and those with an activity score of 1.5, should receive a 50% dose reduction.

An update was also made noting that patients homozygous for the 2846A>T variant may require a dose reduction of greater than 50%. The full update can be read on the CPIC website, as well as on the PharmGKB pages for capecitabine and fluorouracil.

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Read the update and the original guideline on the CPIC website
Read the update and the original guideline on the PharmGKB website (capecitabinefluorouracil)
Read the paper by Henricks et al. in The Lancet Oncology
Read the PharmGKB blogpost on the Henricks et al. paper







Tuesday, December 4, 2018

New biogeographical groups in use at PharmGKB


Recent visitors to the PharmGKB website may have noticed a change in how we report racial and ethnicity information in our variant and clinical annotations. Until July 2018, PharmGKB used the US Office of Management and Budget (OMB) race categories with an additional ethnicity category of Hispanic/Latino. These groups are US-centric, at odds with PharmGKB’s position as an international resource for pharmacogenomic knowledge, and we encountered issues with applying these categories consistently to the global populations described in the pharmacogenomic literature.

To solve these issues, we collaborated with the Bustamante Lab at Stanford University to analyze genetic data from the 1000 Genomes Project and the Human Genome Diversity Project and develop a new grouping system based on biogeographical groups, published in Clinical Pharmacology and Therapeutics. This new system has a total of nine groups; seven geographical groups (American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, Sub-Saharan African) and two groups for African American/Afro-Caribbean and Latino populations which have arisen more recently and are genetically distinct from the seven geographical groups.

The areas covered by the seven geographical groups are shown on the map available in the paper and on this page. Note that these group boundaries are determined by the location of genetic ancestors pre-colonization and pre-Diaspora and do not reflect present-day distribution of people who would belong to each of these groups. The African American and Latino groups exhibit a significant degree of post-colonization and post-Diaspora gene flow between multiple geographical populations and are not shown on the map. 

All nine groups are now being used in PharmGKB curation activities and all existing variant and clinical annotations have been transitioned to this new grouping system. While we encourage pharmacogenomics researchers to consider using this grouping system in their publications in an effort to standardize population reporting across the field of pharmacogenomics research, this system is not intended to be used in place of patient genotypes in the implementation of pharmacogenomics.

You can find more details about our biogeographical grouping system, including detailed descriptions for each group, here. As part of the process of implementing these new groups, we have been reassessing how we tag study populations in curated papers and will be making some more changes in the coming months. All changes will be announced on our blog and our Twitter account @pharmgkb.

Monday, December 3, 2018

New PharmGKB pathways for methylphenidate

PharmGKB released two new pathways for methylphenidate. Methylphenidate is a central nervous system stimulant used for the treatment of attention deficit hyperactivity disorder and narcolepsy and elicits its effects by blocking the reuptake of the neurotransmitter dopamine and norepinephrine into the presynaptic neuron. The pharmacokinetics pathway depicts the metabolism and the pharmacodynamics pathway describes the synthesis, degradation, release and uptake of monoamines, synaptic effectors and targets of methylphenidate. Both summaries discuss the effect of genetic variations on methylphenidate.

View all pathways at PharmGKB

Monday, November 19, 2018

CYP2D6*14A and *14B are updated to *114 and *14 based on the current PharmVar release

PharmGKB and CPIC revised the CYP2D6 allele names *14A and *14B to be in concordance with the latest major PharmVar release

CYP2D6*14A is revised to *114 and *14B to *14 in the variant and clinical annotations. The allele choices in the annotation of the CPIC guidelines for CYP2D6 have been updated to reflect the change.

The Gene-specific Information Tables for CYP2D6 (CYP2D6 allele definition table, CYP2D6 allele functionality table, and CYP2D6 diplotype-phenotype table) have been updated to included the new name assignment.

Monday, November 5, 2018

Major PharmVar update released

PharmVar has announced the release of a major update to www.pharmvar.org. Notable new features include a revised haplotype naming system, the introduction of unique haplotype IDs, a functional impact display next to causative SNVs in brackets and a revised allele (CYP2D6*14A is now *114). The new gene page design has customizable display options and allows the user to see variation info across reference sequences and genome builds and rsIDs without leaving the page.

The update also features nomenclature for the first non-CYP gene, NUDT15. Papers describing the new features, and how NUDT15 nomenclature was developed are close to being published in Clinical Pharmacology and Therapeutics. A presentation with an overview of PharmVar and highlights of the new features can be found under the About tab on the PharmVar website.

PharmGKB will soon be updating our Gene Information Tables for CYP2D6 to reflect the revised allele status of CYP2D6*114. Our NUDT15 Gene Information Tables are already in sync with PharmVar.