Living theragenomic medicine: Direct to consumer test for metabolism of drugs FDA approved

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November 08, 2018 –  The American Food and Drug Administration (FDA) has just authorized the first direct-to-consumer test for detecting genetic variants in genes that may govern the metabolism of drugs in individual patients.

Thus, FDA permits marketing, with special controls, the 23andMe Personal Genome Service Pharmacogenetic Reports test as a direct-to-consumer test and is authorizing the test to detect a total of 33 genetic (allelic) variants (see below) of a selection of genes coding for common drug metabolising enzymes, including CYP2D6, CYP2C19, CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, and SLCO1B1.

The 23andMe Personal Genome Service (PGS) is a qualitative genotyping assessment system applied to genomic DNA isolated from human saliva collected using the Oragene Dx OGD-500.001 to simultaneously detect, report, and interpret genetic variants in a broad multigene test. The assessment system is intended to enable users to access information about their genetics that could aid discussions with a healthcare professional.

Genetic (allelic) variants of genes that code for drug metabolizing enzymes may lead to a classification of indidivual patients into patient subgroups that functionally could be looked at as ultrarapid metabolizer, as normal metabolizer, as intermediate metabolizer, as low metabolizer, and as non-metabolizer of a given drug, i.e., these variants may determine the clinical metabolizer phenotype of an individual patient. These groups of patients would exhibit very different pharmakokinetic properties with respekt to absorption, distribution within the body, metabolism, and excretion (ADME) of a given drug.

They do so, however, only for drugs that are mainly metabolized by one of those enzymes coded for by, for example, the CYP2D6 gene. Thus, it is important to know, if a given drug is a substrate for the gene and the genetic (allelic) variants thereof. For CYP2D6 as an example, there are at least 27 clinically most useful and often used drugs (better yet, pharmacologically active ingredients (PAI), whose major metabolic pathways are governed by CYP2D6, as we can learn from the famous Flockhart Table provided for by Indiana University, Medical School. At the same time does the table list direct inhibitors and inducers of enzymes, both of which may strongly influence, independently from the genetic background, the metabolic fate of a drug. Moreover, PharmKGB is the authoritative source that curates and provides validated knowledge about the impact of genetic variation (i.e., allelic variants) on drug response for researchers, clinicians, and patients alike. PharmGKB provides validated information about which drugs in combination with which allelic variant will have a pharmacologically confirmed effect and therefore result in defined phenotype with respect to metabolism of a given drug in an individual patient, i.e., the carrier of a given allelic variant. This is not an easy task at all. PharmGKB lists currently roughly 500 drug label annotations from US Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency, Japan (PMDA) and Health Canada (Santé Canada) (HCSC) which come with pharmacogenetic information and information on the action to take, before prescribing the given drug to a patient, such as testing required, and others. Likewise, PharmGKB annotates drug dosing guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Royal Dutch Association for the Advancement of Pharmacy – Pharmacogenetics Working Group (DPWG), the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) and other professional societies. These guidelines present the summary of the respective drug dosing in relation to the genetic outfit of the patient (i.e., his genotype).

Only the combination of all this validated and curated information will be productive for the affected patient. In addition, patients (and their physicians) should be aware the just approved 23andMe Personal Genome Service Pharmacogenetic Report is indicated for the reporting of the following gene variants only:

Gene:                      Variant(s):

CYP2C19                *2, *3, *17

CYP2C9                 *2, *3, *5, *6. rs70898580

CYP3A5                 *3

UGTA1A1              *6, *28

DPYD                    *2A, rs7376798

TPMT                   *2, *3C

SLCO1B1              *5

CYP2D6                *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, “15, *17 *20, *29, *35, *40, *41

Consulting a dedicated database for genetic (allelic) variants of the major class of drug-metabolizing enzymes (i.e., CYP’s) however reveals, that, for example for the CYP2D6 gene, there  are 113 allelic variants listed. Similarly, for the CYP2C9 gene, there are 60 allelic variants listed, and for the CYP2C19 gene 35 allelic variants. While all these allelic variants may occur in populations at very varying frequencies, these numbers would indicate that quite many of patients would not be able to get any useful information from the current 23andMe Personal Genome Service Pharmacogenetic Report, because their proper allelic variants, of which they are carriers, are not probed for.

This is somewhat reflected in the announcement by the FDA, which says that while the test is a step forward in making information about genetic variants available directly to consumers and yield better inform for patient’s discussions with their health care providers, the test should not be used to make treatment decisions on their own, and any medical decision should be made only after discussing the results with a licensed health care provider after confirming results using clinical pharmacogenetic testing. For the reasons mentioned above, that leaves still many many patients out.

In addition, patients may have to consider the striking differences in the distribution of genetic variations (i.e., alleles) between populations with important implications for personalized drug therapy and healthcare programs. A recent study illustrates the global distribution map of CYP alleles with clinical importance, based on the analysis of data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population‐specific linkage information, the frequencies of 176 CYP haplotypes, were determined, and just showed the enormous  functional variability of drug metabolism in the respective populations. The 23andMe Personal Genome Service Pharmacogenetic Report(s) do hardly address any of these questions.

See here an introductory video on pharmacogenetic testing related to drug metabolism:

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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