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.

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.

--

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

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.

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

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.

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. 

PharmGKB data used to establish a minimum genetic testing panel for psychiatry

The lack of standardization of which genes or alleles should be included in pharmacogenetic testing panels is a major barrier to the full implementation of pharmacogenomics in the clinic. In an effort to help clinicians select an appropriate pharmacogenetic test, Dr. Chad Bousman and Dr. Abdullah Al Maruf of the University of Calgary and Dr. Daniel Mueller of the University of Toronto gathered available pharmacogenetic evidence from a number of sources, including PharmGKB, CPIC and the Pharmacogene Variation Consortium(PharmVar). This evidence informed the authors’ recommendations of which genes and variants should be included in a minimum pharmacogenetic testing panel for psychiatry.

For inclusion on the panel, a variant drug interaction needed to be associated with a Level 1A or Level 1B Clinical Annotation in PharmGKB, an FDA or EMA drug label which specifically recommended or required pharmacogenetic testing prior to administering the drug and/or a CPIC or DPWG dosing guideline recommendation. Variants also had to be present at a frequency of >1% in at least two of the seven major Human Genome Diversity Project - Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) populations, which are used in the PharmGKB gene information tables. To ensure that the panel could be easily validated, each variant had to have reference material available through the Genetic TestingReference Materials Coordination (GeT-RM) Program.

Starting from a list of 91 drugs which are used in psychiatry, 448 initial gene-drug interactions were identified. Following visualization of the data using a network map showing the strength of evidence for each interaction, 31 drug-gene pairs were determined to have sufficient evidence to warrant their inclusion on the minimum testing panel. The resulting panel, published in Current Opinion in Psychiatry, contains 16 alleles in the genes CYP2D6, CYP2C9, CYP2C19, HLA-A and HLA-B.

The authors emphasize that this panel should be considered a minimum standard for pharmacogenetic testing in psychiatry and that potential gene-gene interactions are not covered. The panel will also need to be regularly updated to include new genes and variants as new guidelines and published evidence become available.

We would like to note a few relevant points about the paper. Given the reliance on our Level 1A/1B Clinical Annotations, it is important to state that some genes with a high level pharmacogenomic association may have variants or alleles which are not covered by a Level 1A or 1B Clinical Annotation, due to a lack of published evidence specifically studying these alleles.  As an example, CYP2D6 has over 100 documented variant alleles.  While PharmGKB has multiple Level 1 Clinical Annotations summarizing associations between CYP2D6 alleles and drugs, not every allele in every diplotype that CPIC provides recommendations for will be represented in our clinical annotations.

It is unclear how exactly information from PharmVar was used in the process of designing this panel. While PharmVar provides a wealth of information about pharmacogenetic allele definition and nomenclature, it does not assign a level of evidence to pharmacogenetic variants in the way that PharmGKB assigns a level of evidence in our Clinical Annotations. The paper also does not explicitly state whether drug labels which recommend or require testing were identified using the PharmGKB drug label annotations or by another method. In any case, we would like to emphasize that the PGx level of drug labels annotated in PharmGKB is determined by PharmGKB curators rather than any regulatory body.

Readers should also note that using allele frequencies as a condition for inclusion on a testing panel will, by definition, result in rare pharmacogenetic alleles remaining undetected in patients.

Further information about the levels of evidence assigned to our Clinical Annotations can be found here while information about the PGx levels assigned to our annotated drug labels can be found here. You can access annotated drug labels and annotated CPIC and DPWG guidelines through the PharmGKB website.

DPYD genotyping implementation study published

In a journal article published online last week in The Lancet Oncology, Henricks et al. reported that DPYD genotype-based dose reductions of fluorouracil and capecitabine in cancer patients resulted in improved safety outcomes and was feasible in clinical practice. 

The authors prospectively genotyped four DPYD variants: rs3918290 (1905+1G>A; DPYD*2A), rs55886062 (1679T>G; DPYD*13), rs56038477 (1236G>A; haplotype B3) and rs67376798 (2846A>T). Heterozygous DPYD variant allele carriers for rs3918290 and rs55886062 received an initial dose reduction of 50%. Heterozygous variant allele carriers for rs56038477 and rs67376798 received an initial dose reduction of 25%, since these variants result in moderately reduced DPYD activity. Wild-type patients were treated according to the current standard of care, and homozygous or compound heterozygous variant allele carriers were excluded.

Results showed that the genotype-guided dosing reduced the risk of severe fluoropyrimidine-related toxicity in patients carrying the rs3918290, rs55886062 and rs67376798 variants, though patients carrying the rs67376798 variant still had an increased risk for toxicity compared with wild-type patients. Carriers of the rs56038477 variant did not have a reduction in severe toxicity. The authors concluded that a dose reduction of 25% in patients with rs56038477 and rs67376798 variants was not sufficient to lower the risk of severe toxicity, and suggested that a larger dose reduction may be required. 

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for DPYD genotype-guided fluoropyrimidine dosing recommend a dose reduction of 50% in heterozygous carriers of the rs3918290 and rs55886062 variants. However, they do not recommend an exact dose reduction for heterozygous carriers of the rs56038477 and rs67376798 variants, rather, they suggest a range of 25-50%. This lack of specificity was due to limited evidence for genotype-guided dosing of these variants. However, Amstutz and Largiadèr, in their accompanying commentary, suggest that the Henricks et al. study  provides evidence to support a recommendation for a 50% dose reduction in all heterozygous variant allele carriers. Amstutz and Largiadèr also note that 8% of white patients carry one of these four variants, meaning that the benefits shown in this study affect a substantial proportion of patients treated with fluoropyrimidines. 

---

Read the original journal article and the commentary on the article

Read the CPIC dosing guideline for DPYD and fluoropyrimidine dosing

Read the DPWG dosing guidelines for fluorouracil and capecitabine

Read the PharmGKB annotations of the CPIC dosing guideline for fluorouracil and capecitabine