New CPIC Guideline: CYP2B6 and efavirenz

The CPIC Guideline for CYP2B6 and efavirenz is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB pages for efavirenz, CYP2B6, and on the CPIC website.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor widely used worldwide to treat HIV-1 infection. It is predominantly metabolized into inactive metabolites by cytochrome P450-2B6 (CYP2B6). Genetic variants in CYP2B6 (eg. CYP2B6*6 and *18), along with other genetic and non-genetic factors, are known to influence variability in efavirenz response. Patients with certain CYP2B6 genetic polymorphisms may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. 

The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for efavirenz based on CYP2B6 genotype. For therapeutic recommendations and further details, please refer to the CPIC Guideline for CYP2B6 and efavirenz-containing antiretroviral therapy.

PharmGKB opinion piece on pharmacogenomic RCTs published in Clinical Pharmacology and Therapeutics

Is supporting evidence from a randomized controlled trial (RCT) always necessary when implementing pharmacogenomics in the clinic? In an opinion piece authored by members of the PharmGKB team and published in Clinical Pharmacology and Therapeutics, we argue that an overreliance on evidence from RCTs is not beneficial to pharmacogenomic implementation.

An insistence that RCT evidence is made available prior to implementation assumes that RCTs will eventually be carried out for every actionable gene-drug pair. This is an unrealistic assumption, especially in the case of generic drugs. We also question why other factors which can influence drug clearance in a patient, such as hepatic or renal impairment, are easily incorporated into clinical care without RCT evidence while pharmacogenomics is held, seemingly arbitrarily, to a different standard.

There are also significant issues with pharmacogenomic RCTs, in terms of cohort diversity, adequate allele representation and statistical power; all of which can have serious, even fatal, consequences for patients. Furthermore, a reliance on evidence from RCTs overlooks the substantial evidence base from other studies, much of which is curated in PharmGKB. Evidence from non-RCT studies already informs clinical guidelines from international consortia, including CPIC and the DPWG.

The paper is available online and will be included in an upcoming special issue of Clinical Pharmacology and Therapeutics. Dr. Andrea Gaedigk of Children’s Mercy Kansas City, and leader of the PharmVar consortium, will be the guest editor of this issue.

CYP2C19 testing may assist with prescribing sertraline and escitalopram

Mary Relling (St. Jude Children's Research Hospital) and I (Teri Klein) as Co-Principal Investigators of the Clinical Pharmacogenetics Implementation Consortium (CPIC) have been discussing the letter that the FDA recently sent to a genomics laboratory expressing concern that “providers may make inappropriate treatment decisions based” on pharmacogenetic testing offered by that lab. The FDA specifically highlighted that “the relationship between CYP2C19 genotype and drug response to escitalopram and sertraline is not established.”

While it is true that some pharmacogenomic testing laboratories may be including genetic variants in their tests, along with prescribing advice, that do not have adequate evidence for clinical utility, testing for variants in this particular gene does have utility for prescribing decisions for escitalopram and sertraline. In fact, CYP2C19 phenotypes are specifically included as actionable for these 2 drugs in CPIC’s Guideline for SSRIs.

Many CPIC guidelines encompass gene/drug pairs for which the mechanism of gene/drug association is pharmacokinetic in nature; therefore, gene-based dosing in these cases is analogous to medication dose adjustments that are routinely made on the basis of renal or hepatic function or due to drug-drug interactions, most of which are supported by mechanistic evidence rather than clinical trial data. The drug labels for both sertraline and escitalopram include recommendations for reduced dosages in hepatic impairment, based on similar mechanistic pharmacokinetic considerations as apply to CYP2C19 status, and presumably without randomized clinical trial-level “evidence.” Using genotype to evaluate CYP2C19 metabolism is certainly more relevant to hepatic metabolism of these agents than is using nonspecific clinical markers of “hepatic impairment.”

CPIC assigns an evidence level of A, B, C, or D to gene/drug pairs, with CPIC levels A and B deemed to have actionable prescribing based on genetics; importantly, gene/drug pairs with a CPIC level of C or D are not considered to have adequate evidence to support using a genetic test for prescribing, and this can serve as a useful starting point in deciding whether clinical genetic testing of that gene for that drug is likely to be justified.

In FDA’s warning letter, it is stated that “providers may make inappropriate treatment decisions based on these test results, including inappropriate dosing adjustments, prescribing an ineffective therapy, and not prescribing a therapy that could benefit the patient.” The same criticism could apply to any test result, even for the liver function tests that are already included in the FDA approved labels for these drugs. We agree that prescribers should be warned about the impact of hepatic function on drug effects; we advocate that pharmacokinetically based genetic tests may also be worthy of consideration by prescribers. Such a useful pharmacokinetically based genetic test includes use of CYP2C19 testing to assist with prescribing sertraline and escitalopram.

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.

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.

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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 (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.