ESPT conference and PGx future research directions

I want to share my thoughts on what I learned from the excellent presentations at the ESPT conference. Pharmacogenetics is both science and art.

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The Science:

While the results of large-scale pharmacokinetic studies confirmed the role of pharmacogenetic effects, it was noted that there was very high variability of drug metabolic ratios in CYP2C6, CYP2C19 Normal metabolizers, and to some extent in Ultrarapid metabolizers. Several speakers talked about drug-induced phenoconversion of the CYP2D6 activity that frequently explains the discordance between PGx-predicted and actual metabolic activity.?

However, for other CYP enzymes, the correlation between PGx-predicted and actual metabolic activity is much lower. This phenomenon has two explanations:

1.???? There are still many rare yet uncharacterized functional variants in CYP enzymes, that lead to misclassification of some individuals as “Normal” metabolizers, while in fact, these are Intermediate/Poor or perhaps Rapid metabolizers.

2.???? CYPD6 is the only non-inducible cytochrome. So, the environmental impact on the activity of other CYP enzymes is greater for genetically Normal and Rapid metabolizers.

The first issue is addressed through deeper genetic analysis by sequencing (PacBio, Oxford, Illumina, ThermoFisher) or high-resolution PGx-optimized arrays (Illumina GDA-PGx or Axiom arrays).

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The second factor is an interesting area of research:

Caroline Samer and colleagues used the “Geneva cocktail” of six micro-dosed drugs to study phenoconversion in various states. I attached here the published studies in COVID-19 patients, surgery and other settings that show the impact of acute and chronic inflammation on CYP activity:

1. Reduction of >50% for CYP3A4, CYP2C19 and CYP1A2 metabolic activity.
2. 120% increase for CYP2B6 and ~80% increase in CYP2C9 expression.?
3. CYP2D6 activity is largely unchanged (as a non-inducible enzyme).

Note that these changes do not apply to Poor and lower-extent Intermediate metabolizers. Gender-specific and age effects were also discussed, but the current data is insufficient.

Caroline Samer revealed that their group identified “endogenous” metabolites coming from coffee (CYP1A2), potato (CYP2D6) and other foods that they now can use as markers for measuring actual metabolic activity to study the impact of drug-drug, drug-gene, and drug-condition interactions.

Other presenters aimed to identify additional genes impacting the expression and function of CYP enzymes through pharmacokinetic GWAS studies. These exciting findings require independent replications in larger cohorts to assess these variants' clinical validity and utility.

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While some PGx testing providers have already incorporated phenoconversion for CYP2D6, more robust phenococonversion models are required for all major CYPs. We are eagerly awaiting the results of these studies to develop comprehensive and robust phenoconversion algorithms that will account not only for drug-induced phenoconversion but also for patient’s health status.

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The Art of Pharmacogenetics:

While many speakers presented various PGx implementation models, it was evident that the main question of Who and When should be offered a PGx test remains open.

National genome sequencing projects deliver great research; the main barrier is making the PGx data easily accessible to prescribers and patients when therapeutic decisions are made. ?Administrative barriers and a lack of informatics infrastructure create artificial barriers and reduce the practical utility of genomic data, especially outside of academic hospitals' walls.

Some jurisdictions, including the UK, are still going through narrowly defined clinical settings with PGx implementation in oncology and cardiology that limit the scope of testing only to one gene at a time.

While the U-PGx results on the value of PGx panel testing, the lack of limited reimbursement and inconsistent and cumbersome patient onboarding pathways are the remaining barriers to the routine application of PGx in primary care.

In Spain, where the national health authority decided to provide universal coverage of PGx testing, clinical researchers led by Adrián Llerena focus on collecting patient-reported side effects to help refine PGx associations. Unfortunately, this was the only group (besides Pillcheck in Canada) that emphasized the importance of patient-reported outcomes and medication experience.

I was also proud to see that the Pillcheck platform is a more scalable and complete PGx-medication management solution enabling the collection of patient-reported medication experiences compared with well-funded national genome projects.?

Lastly, thank all presenters for sharing valuable insights and Ron H.N. van Schaik for organizing such a wonderful event.

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