How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial

Abstract

CYP2D6 genotype is increasingly being integrated into practice to guide prescribing of certain medications. The CYP2D6 drug metabolizing enzyme is susceptible to inhibition by concomitant drugs, which can lead to a clinical phenotype that is different from the genotype‐based phenotype, a process referred to as phenoconversion. Phenoconversion is highly prevalent but not widely integrated into practice because of either limited experience on how to integrate or lack of knowledge that it has occurred. We built a calculator tool to help clinicians integrate a standardized method of assessing CYP2D6 phenoconversion into practice. During tool‐building, we identified several clinical factors that need to be considered when implementing CYP2D6 phenoconversion into clinical practice. This tutorial shares the steps that the University of Florida Health Precision Medicine Program took to build the calculator tool and identified clinical factors to consider when implementing CYP2D6 phenoconversion in clinical practice.

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof‐of‐concept study

“…16 Furthermore, we also built models where patients’ phenotype was converted prior to multivariable adjustment by multiplying the patients’ CYP2D6 activity scores by factors of 0.5 and 0 for the concomitant intake of moderate and strong CYP2D6 inhibitors, respectively. 17 CYP2D6 genotype‐inferred phenotype was treated as an ordinal variable and coded as 0, 1, 2, or 3 for PM, IM, NM, and UM, respectively. Although inferred phenotypes are widely used in PK association studies, 18 , 19 , 20 as a sensitivity analysis, we also assessed a single key variant of CYP2D6*4 , rs3892097, which is prevalent within populations of European descent.…”

“…We referred to the US Food and Drug Administration (FDA) Table of Inhibitors to provide an objective list of such medications to consider 16 . Furthermore, we also built models where patients’ phenotype was converted prior to multivariable adjustment by multiplying the patients’ CYP2D6 activity scores by factors of 0.5 and 0 for the concomitant intake of moderate and strong CYP2D6 inhibitors, respectively 17 . CYP2D6 genotype‐inferred phenotype was treated as an ordinal variable and coded as 0, 1, 2, or 3 for PM, IM, NM, and UM, respectively.…”

Sub-Analysis of CYP-GUIDES Data: Assessing the Prevalence and Impact of Drug-Gene Interactions in an Ethnically Diverse Cohort of Depressed Individuals

“…This potential confounder involving drug-drug interactions can ultimately influence the prevalence of DGIs and treatment response. For example, concomitant administration of medications such as bupropion, fluoxetine and paroxetine which are CYP2D6 inhibitors could result in an adjusted CYP2D6 phenotype that is different to genotype-based prediction of drug metabolism ( Owen et al, 2009 ; Cicali et al, 2021 ; Hahn and Roll, 2021 ). Another limitation in our sub-analysis includes the small number of patients restricting additional data analyses related to RAR and race/ethnicity ( Ruaño et al, 2020 ).…”

Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2D6/CYP2C19 genes play a role? A UK population-based study

“…We adjusted for strong/moderate inhibitors (e.g., paroxetine and quinidine for CYP2D6 and fluoxetine and fluvoxamine for CYP2C19), as they play a major role in phenoconversion, a phenomenon whereby drug-gene or drug-drug-gene interactions may result in an observed phenotype different from the geneticallypredicted phenotype. 35 We did not adjust for BMI in order to avoid the risk of overadjustment bias. 36 Effect estimates are reported with 95% confidence intervals (CIs) and uncorrected p values in tables and forest plots.…”