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.

Figure 1:. University of Florida Health Precision Medicine Program Phenoconversion Method

After reviewing the literature for various phenoconversion approaches, the UF Health Precision Medicine Program adapted a method endorsed by the Clinical Pharmacogenetics Implementation Consortium. The steps of this method are outlined in the figure.

Figure 2:. Phenoconversion Application Algorithm

The three common rules identified for predicting phenoconversion [ 1) Poor metabolizers do not undergo phenoconversion in presence of a CYP2D6 inhibitor. 2) When a strong inhibitor is present, the clinical phenotype will always be a poor metabolizer. 3) When a moderate inhibitor is present, the clinical phenotype will only change for certain genotype-based activity scores] were utilized to create an algorithm that served as the foundation to build the automated calculator tool.

Figure 3:. Original and Final Versions of the CYP2D6 Calculator (Alpha version)

The calculator tool underwent several revisions during the build process to incorporate complicating clinical factors and user-feedback. The left side of the figure shows the original version, where the user had to calculate and enter their own genotype-based activity score. The right side of the figure shows the final version of the calculator, where the user selects their patient’s CYP2D6 alleles and then the calculator determines the genotype-based activity score. This is reflective of the alpha version that will be used in the IGNITE II trials.