Wednesday, December 14, 2016

CPIC Guideline Update: CYP2D6, CYP2C19 and tricyclic antidepressants (TCAs)

The 2016 update of the guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) regarding the use of pharmacogenetic tests for CYP2D6 and CYP2C19 in dosing tricyclic antidepressants (TCAs) have been accepted for publication in Clinical Pharmacology and Therapeutics. The accepted article can currently be viewed on the PharmGKB and CPIC websites. 

TCAs are mixed serotonin and norepinephrine reuptake inhibitors used to treat depression and several other disease states.
The 2016 guideline update provides dosing recommendations:
  • for TCAs based on CYP2D6 phenotype
  • for TCAs based on CYP2C19 phenotype
  • for amitriptyline based on both CYP2D6 and CYP2C19 phenotype.
Amitriptyline and nortriptyline are used as representative TCAs because the majority of pharmacogenomics studies have been published on these drugs. However, TCAs have comparable pharmacokinetic properties and it it may be reasonable to apply the recommendations to other TCAs.

For further details see the guidelines and supplement at PharmGKB and CPIC.

Thursday, December 8, 2016

New CPIC Guideline - CYP2C19 and voriconazole

Guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) regarding the use of pharmacogenetic tests of CYP2C19 for voriconazole prescribing decisions have been accepted for publication in Clinical Pharmacology and Therapeutics. The accepted article can currently be viewed on the PharmGKB or CPIC websites.

Voriconazole is a triazole antifungal agent active against a variety of fungi and molds, such as Candida, Aspergillus, Fusarium and Cryptococcous. However, it is particularly recommended for pulmonary invasive aspergillosis, an infection that primarily occurs in immunocompromised patients. CYP2C19 is the primary enzyme responsible for the metabolism of voriconazole, and variations within the CYP2C19 gene have been shown to affect exposure to voriconazole. CYP2C19 ultrarapid or rapid metabolizers may have decreased voriconazole exposure, affecting the ability to achieve therapeutic concentrations, while poor metabolizers may have increased exposure, affecting the risk for adverse effects.

For therapeutic recommendations and further details, please refer to the CPIC Guideline for CYP2C19 and Voriconazole Therapy on the PharmGKB or CPIC websites.

Monday, December 5, 2016

New and Updated PMDA label translations now available

New translations of package inserts from the Pharmaceutical and Medical Devices Agency (PMDA), Japan, as well as updated translations of existing package inserts, are now available on PharmGKB.

The PMDA is a regulatory agency responsible for scientific reviews for the approval of drugs or medical devices, as well as safety monitoring after approval. The PMDA website provides PDF copies of package inserts for approved drugs, though these inserts are only available in Japanese. Previously, PharmGKB had used a 2013 paper by Shimazawa and Ikeda that selected PMDA inserts to examine for PGx information based on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling as it existed on October 2012, and then provided translations of any PGx information present in the PMDA package inserts. Though this paper was useful, additional drug labels with PGx information have been added to the FDA table in the past 4 years, and PharmGKB has also identified drug labels with PGx information independently. 

Now, through a collaboration with the Japanese Society of Pharmacogenomics, as well as Silicon Valley Tech KK, PharmGKB is able to provide translations of a wider set of PMDA labels, as well as more extensive translations of some labels. 

Some of the new labels available include:

Methylene Blue

An overview of all the drug labels on PharmGKB can be viewed here

PharmGKB thanks the Japanese Society of Pharmacogenomics for its diligent work in translating these labels, and helping to make them available to the public.

Friday, November 18, 2016

Very Important Pharmacogene (VIP) summary for MT-RNR1 published in Pharmacogenetics and Genomics

The PharmGKB review of the MT-RNR1 gene has been published in the December issue of Pharmacogenetics and Genomics. MT-RNR1 is a mitochondrial gene that codes for ribosomal RNA (rRNA). Variations within this gene, particularly rs267606617 (1555A>G), are strongly associated with the development of hearing loss following administration of aminoglycoside antibiotics. Indeed, over 40 studies have found that 100% of individuals with the G allele at this variant developed hearing loss after receiving aminoglycosides, a class of antibiotics that includes streptomycin and gentamicin, among others. Several other variations in this gene are also associated with hearing loss following aminoglycoside treatment.

The full Very Important Pharmacogene (VIP) review can also be viewed on the PharmGKB website. In addition to discussing the pharmacogenetics of MT-RNR1, it also provides a brief overview of the mitochondrial genetic system as well as the anatomy of the ear and types of hearing loss.

Wednesday, October 26, 2016

Upcoming change to user accounts

We will be making a small change to user accounts this weekend that should make our users’ lives a little easier. Registered PharmGKB users will no longer be required to have a username as part of their profile. Instead, users will be able to log into the site and manage their profile using their registered email address.

Existing users, you will be able to sign in using your existing username or your email address (along with your password, of course). Please make sure your email address in your profile is current and active. Usernames will be completely phased out in a later update and we will notify you before it happens.

New users, you will no longer be asked to come up with a unique username when registering for an account. That’s one less thing to remember.

Registering as a user of PharmGKB and accepting our data usage agreement enables you to view all the information in our curated Clinical Annotations and Variant Annotations on the site.

Send a message to feedback if you have questions about this account update.

Tuesday, September 27, 2016

Coverage of PharmCAT in GenomeWeb

In April 2016 and August 2016 we blogged about the development of PharmCAT and its presentation at the American Society of Human Genetics (ASHG) annual meeting in October.

The Pharmacogenomics Clinical Annotation Tool (PharmCAT) is a software tool to extract all CPIC level-A variants from a genetic dataset (represented as a vcf), interpret the variant alleles, and generate a report. It is currently being developed in a collaboration between the PGRN Statistical Analysis Resource (P-STAR), the Pharmacogenomics Knowledgebase (PharmGKB), the Clinical Genome Resource (ClinGen), and CPIC.

For further coverage about PharmCAT, read the article by Julia Karow on September 26th in GenomeWeb: Researchers Hope PharmCAT Tool Will Help Improve ClinicalImplementation of Pharmacogenomics.

Monday, September 26, 2016

Response to the American Academy of Pediatrics statement on codeine: let's consider CYP2D6

The American Academy of Pediatrics (AAP) issued a statement last Tuesday that codeine should not be used in children. As discussed in the article, pharmacogenetic variation can affect response to codeine, which is metabolized into its active form by the hepatic enzyme CYP2D6. Thus poor metabolizers are unlikely to benefit from codeine, and ultrarapid metabolizers can experience high concentrations of morphine that may result in respiratory depression or sleep apnea even at normal codeine doses.

While we agree that the variability in patient response to codeine is important to consider, we feel that the AAP did not give enough credit to the power of CYP2D6 genotyping prior to treatment. The article devotes only two sentences to the possibility of pre-emptive genotyping, saying “although CYP2D6 genotyping that could identify patients at higher risk is available (although currently expensive), patients with normal metabolism are also at theoretical risk of high morphine levels. Therefore, further investigation is required to determine the value of such testing, which will depend on the population in whom it is applied.”

It is unclear what is intended by the claim that “patients with normal metabolism are also at theoretical risk of high morphine levels”, as no citation is provided. Patients who are CYP2D6 normal metabolizers are expected to have normal morphine formation. Furthermore, codeine is still an appropriate and effective drug choice in the majority of cases, regardless of the population. As the AAP statement points out, ~29% of African/Ethiopian, ~21% of Saudi Arabian and other Middle Eastern, and ~3.4 - 6.5% of African-American and Caucasian patients are expected to be ultrarapid metabolizers, with even lower frequencies of poor metabolizers, meaning that the majority of patients will receive the intended benefit from codeine treatment, contrary to what one doctor was quoted as saying in at least two media outlets (another article here). 

While pharmacogenetics is still in the early stages of clinical adoption, it can be an effective tool for improving patient therapy, particularly when drug alternatives are not simple. In the case of codeine, the official AAP statement urges caution in using alternative analgesics, including oxycodone, hydrocodone, and tramadol, because they also are metabolized to some degree by CYP2D6 (though more than one public media article presented comments by one of the statement authors suggesting that hydrocodone or tramadol be used instead of codeine, without any caveats). Instead, AAP suggests NSAIDs for mild to moderate pain, and an IV drip for greater pain, though these therapies also require clinician education to avoid postoperative bleeding. If further education is required to deliver care, why does this curriculum not consider CYP2D6 pharmacogenetic information, which could make the effects of codeine more predictable and restore its value as an analgesic? As for an alternative to the antitussive properties of codeine, CBS and CBS local New York suggested that popsicles or honey be used.

We are concerned about the misinformation and creative interpretations related to the AAP statement that have been communicated in public media. Chicago Tonight reported that “children are among those considered to be ‘ultra-rapid metabolizers’ of codeine”, which implies to readers that all children are CYP2D6 ultra-rapid metabolizers; they are not. Similarly, a Huffington Post article stated that “children are specifically less capable of metabolizing codeine than adults because the enzyme changes as the body matures into adulthood.” While functional CYP2D6 activity is not appreciably expressed in fetal liver, it increases rapidly after birth, and CYP2D6 genotype is expected to be equally reliable for inferring phenotype in children as it is in adults.

CPIC has published a freely downloadable guideline for adjusting codeine therapy based on CYP2D6 genotype.  The guideline recommends using alternative therapies -- specifically not hydrocodone or tramadol, which are also metabolized by CYP2D6 to some degree -- in patients with genotypes predicting poor and ultra-rapid metabolizer status. The “black box” warning on the FDA label for codeine can also be viewed at PharmGKB.

In the meantime, please pass the medical-grade popsicles.

Thursday, September 22, 2016

Clinical implementation of PGx discussed in JAMA article

A recent article in the Journal of the American Medical Association (JAMA) discusses the current state of pharmacogenetic (PGx) implementation in the clinic. The article notes that clinical uptake of pharmacogenetics has been slow, despite data from the American Medical Association showing that 98% of the more than 10,000 physicians surveyed agree that drug responses may be influenced by genetic variations. This may be due to a lack of implementation guidance and clinical outcome data. Dr. Mary Relling, co-chair of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and chair of the pharmaceutical sciences department at St Jude Children's Research Hospital, is interviewed, and discusses the lack of guidance on FDA labels that contain PGx information, which PharmGKB has previously blogged about. The article also provides an overview of CPIC and its role in providing implementation guidance to clinicians. Dr. Julie Johnson, dean and distinguished professor at the College of Pharmacy at the University of Florida, is interviewed about her Implementing Genomics in Practice (IGNITE) network project, which tracks pharmacogenetic implementation metrics and clinical outcomes, among other areas of research. The article also includes a discussion with Dr. Muin J. Khoury, director of the Office of Public Health Genomics (OPHG) at the Centers for Disease Control and Prevention, on the need for more clinical utility and outcome data for PGx gene-drug pairs. Background on the field of pharmacogenetics is provided, as well as interviews with multiple other leaders in the PGx space, including Dr. Peter H. O'Donnell, associate director for clinical implementation at the University of Chicago's Center for Personalized Therapeutics.

Wednesday, September 21, 2016

Ivacaftor pathway, pharmacokinetics/pharmacodynamics published in Pharmacogenetics and Genomics

The PharmGKB summary of the pharmacokinetics and pharmacodynamics of ivacaftor has been published in Pharmacogenetics and Genomics. Ivacaftor is approved for use in patients who carry particular variants in the CFTR gene. By repotentiating the CFTR ion channel, ivacaftor targets the underlying cause of some forms of cystic fibrosis. Ivacaftor is metabolized by CYP3A4 and CYP3A5 and inhibits ABCB1. Its metabolites are excreted through the transporter SLCO1B1. 

A stylized illustration of the PK/PD pathways of ivacaftor accompanies the publication, and can also be viewed on the PharmGKB website. The illustration and text also includes lumacaftor, a drug that is sometimes used in conjunction with ivacaftor to treat patients with CFTR variants that result in localization defects. The full text and pathway image can be found on the pharmgkb website at