New CYP2C9 Testing Guidelines Published by AMP

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The Association for Molecular Pathology (AMP) has published its consensus, evidence-based recommendations to aid design and validation of clinical CYP2C9 assays, promote standardization of testing across different laboratories and improve patient care. The report, “Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists,” was released online ahead of publication in The Journal of Molecular Diagnostics.

CYP2C9 is a member of the CYP2C subfamily of the cytochrome P450 enzymes, and one of the most abundant and important drug metabolizing enzymes. It acts on approximately 15% of drugs in current clinical use, including ibuprofen and the blood thinner warfarin. As a result, it is currently included in the Food and Drug Administration (FDA) Table of Pharmacogenetic Biomarkers in Drug Labeling for several FDA-approved drugs. There are multiple tests for CYP2C9 currently available.

The AMP Pharmacogenetics (PGx) Working Group has been developing a series of guidelines to help standardize clinical testing for frequently used assays such as CYP2C9. These guidelines were developed with the College of American Pathologists (CAP) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). This latest report follows a set of recommendations for clinical CYP2C19 genotyping allele selection that was previously published in May 2018. The document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing.

“The AMP PGx Working Group started with CYP2C19 and CYP2C9 genotyping panels due to the widespread adoption of these tests and our desire to help physicians, pharmacists, researchers, and other stakeholders better understand what these panels include and what the test results mean,” said Victoria M. Pratt, PhD, FACMG, Associate Professor, Director of Pharmacogenetics and Molecular Genetics Laboratories, Indiana University School of Medicine, AMP President and PGx Working Group Chair. “Since these genes are involved in the phase I metabolism of many commonly prescribed medications, this series of recommendations should be implemented with other clinical guidelines such as those issued by CPIC, which focus primarily on the interpretation of genotyping results and therapeutic recommendations for specific drugs.”

The two-tier categorization of CYP2C9 alleles uses criteria such as allele frequencies in different populations and ethnicities, the availability of reference materials and other technical considerations. The AMP PGx Working Group recommended a minimum set of alleles and their defining variants that should be included in all clinical CYP2C9 PGx tests — Tier 1. The team also defined a Tier 2 list of optional CYP2C9 alleles, which do not currently meet one or more of the criteria for inclusion in Tier 1. These recommendations are offered as a reference guide.

The Tier 1 alleles recommended for clinical testing were selected based on their reported clinical relevance for CYP2C9-associated medications, their frequency, and the availability of reference materials. Tier 1 alleles include: CYP2C9 *2, *3, *5, *6, *8 and *11CYP2C9 *2 and *3 are the most common alleles in Caucasians and Asians and have been extensively investigated among CYP2C9-metabolized medications with narrow therapeutic ranges, such as warfarin and phenytoin. Similar data exist for the *5, *6, *8, and *11 alleles, which occur predominately in people of African descent.

“Pharmacogenetics is a rapidly changing field, and we intend to update these recommendation documents as new data and/or reference materials become available,” said Karen E. Weck, MD, Professor of Pathology and Laboratory Medicine, Professor of Genetics and Director, Molecular Genetics and Pharmacogenomics at University of North Carolina Chapel Hill, AMP President-Elect and PGx Working Group Member. “AMP members are among the early adopters of molecular diagnostic testing in clinical settings, and we are committed to continuously improving professional practice and patient care.”

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