PharmGKB papers in the February 2020 issue of Pharmacogenetics and Genomics

The February 2020 issue of Pharmacogenetics and Genomics has a PharmGKB double feature, with the publication of our sertraline pathway and our VIP summary for CACNA1S.

The sertraline pharmacokinetic pathway, written by Scientific Curator Dr. Rachel Huddart and collaborators, is featured on the cover of the journal. Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is used in the treatment of some psychiatric disorders, such as major depressive disorder. Metabolism of sertraline in the liver by CYP2C19 forms the basis of clinical guidelines from CPIC and the DPWG.

CACNA1S is a subunit of the dihydropyridine receptor and is expressed in skeletal muscle, where it plays a role in muscle contraction. Variants in CACNA1S have been linked to a number of myopathies as well as malignant hyperthermia, which can occur in some patients when exposed to inhaled anesthetics. The recent CPIC guideline forinhaled anesthetics includes recommendations based on CACNA1S variants. Our VIP summary, written by Senior Scientific Curator Dr. Katrin Sangkuhl with Dr.Robert Dirksen of the University of Rochester and former PharmGKB curator Maria Alvarellos, outlines the role of CACNA1S in both normal muscle function and in disease genetics. Key variants which have been associated with malignant hyperthermia are discussed in detail.

Both the sertraline pathway and CACNA1S VIP summary can be accessed on the PharmGKB website.

CPIC launches second Term Standardization project – seeking PGx experts

CPIC leadership has put out a call for gene experts to participate in the second CPIC Term Standardization project, which will begin in early 2020.

This project continues the work of the first term standardization effort in 2016, where standardized terms for pharmacogenetic (PGx) allele function and associated phenotypes were developed and agreed upon by a Delphi process (see Caudle et al. 2017 for further details). The work of the previous project was adopted by many external groups and has helped build consensus between different PGx testing platforms, PGx implementation processes and scientific publications.

The second Term Standardization project will use the same Delphi process to find drug-agnostic allele function and phenotype terms that can be used by pharmacogenes not included in the 2016 work, including VKORC1, RYR1, mt-RNR1 and others. As with the first term standardization project, iterative surveys will be used to find consensus among the group. It is expected that 2-4 rounds of surveys will be needed to achieve consensus. As with the 2016 project, the resulting standardized terms will be published in a peer-reviewed journal and used in future CPIC guidelines.

If you meet the criteria below and would like to join this expert panel, please take this survey (5-10 minutes) to be included in the project. Further information can also be found at the CPIC website.

• Clinician with a working knowledge of pharmacogenetics (pharmacists, physicians, nurses, genetic counselors, etc).

• Researcher with at least 2 years of PGx research experience

• Clinical laboratory scientist or staff with at least 2 years of PGx experience

• EHR standards expert/medical informatic (PGx experience not required but involvement in HL7 or similar experience preferred)

• Gene specific experts and/or CPIC or DPWG guideline author for the following genes to be included in this project: RYR1, CACNA1S, CFTR, G6PD, IFNL3, mt-RNR1, GBA, NAGS, HPRT1, POLG, COMT, OPRM1, SCN1A, SLC6A4, F5, ABL2, ASL, ASS1, CPS1, and OTC

Call for clarification on antidepressant pharmacogenomics

A new Perspective in Clinical Pharmacology and Therapeutics outlines the need for improved communication from pharmacogenomic testing companies and regulators on the role of pharmacogenomics in antidepressant therapy.

Beginning antidepressant treatment can be an arduous experience for patients. Some patients fail to respond to first-line antidepressants, leading to an iterative process of trying different medications until depressive symptoms improve, while others experience antidepressant-induced adverse effects. This current situation highlights the need to make evidence-based improvements to the drug selection and dosing process.

Some pharmacogenomic information is included on the US Food and Drug Administration (FDA)-approved labels of a number of antidepressants. However, the actionability of this information can vary widely between labels and there is no guidance to clinicians on when to seek pharmacogenomic testing for a patient. PharmGKB assigns a PGx Level and tags to our drug label annotations to help users easily recognize labels containing actionable pharmacogenomic information such as recommendations for dose or altered drugs.

The publication’s authors, including Dr. Teri Klein and Dr. Katrin Sangkuhl (PharmGKB and CPIC), Dr. Andrea Gaedigk (PharmVar), as well as Dr. Kelly Caudle and Dr. Roseann Gammal (CPIC), argue that the inconsistencies in drug labels combined with the FDA’s recent communications on the safety and validity of pharmacogenomic testing has created confusion among clinicians and patients about pharmacogenomics in antidepressant prescribing. They also highlight the work of CPIC in producing evidence-based clinical guidelines that can be used to guide drug selection and dosing. In particular, the CPIC guidelines for selective serotonin reuptake inhibitors and tricyclic antidepressants are based on the critical review of decades of scientific evidence.

The article ends with a call for clarity on the level of evidence required to implement pharmacogenomic-guided prescribing in the clinic, particularly with reference to sertraline and escitalopram.