PII-010 - EVALUATION OF PLASMA BIOMARKERS TO ASSESS THEIR ABILITY TO PREDICT CYP2D6 ACTIVITY IN INDIVIDUALS INCLUDING PATIENTS WITH TYPE 2 DIABETES.

V. Michaud^1,2,3, S. Rhiani⁴, M. Arwood⁵, F. Gaudette³, J. Chiasson^6,7, J. Turgeon^5,2; ¹GalensuRX Inc., Orlando, FL, USA, ²Faculty of Pharmacy, University of Montreal, Montreal, Qc, Canada, ³Centre de Recherche du CHUM (CRCHUM), Montreal, Qc, Canada, ⁴U Maryland, Baltimore, MD, USA, ⁵GalenusRx, Orlando, FL, USA, ⁶Faculty of medicine, University of Montreal, Montreal, Qc, Canada, ⁷Centre de recherche du CHUM, Montreal, Qc, Canada.

Background: CYP2D6 activity shows substantial inter- and intra-individual variability. Use of biomarkers could enable more personalized drug treatments and improve dose adjustments with less risk for the patient compared to the traditional phenotyping approach using probe drugs. Recent metabolomic studies have identified potential endogenous candidate markers of CYP2D6 activity. The aim of this study was to explore the validity of potential CYP2D6 biomarkers in adults with and without type 2 diabetes (T2D).

Methods: In this clinical study (NTC02291666), 73 subjects (n= 35 no T2D subjects; n= 38 with T2D) were genotyped and phenotyped for CYP2D6 using the metabolic ratio dextromethorphan/dextrorphan (MR DM/DX). Five biomarkers m/z 220.1543, m/z 416.3159, m/z 432.3108, m/z 444.3108, and m/z 597.3382 were tested as a surrogate of CYP2D6 activity. Plasma biomarker concentrations were measured using LC-HRMS/MS assay and were subsequently correlated with MR DM/DX.

Results: Utilizing the CYP2D6 activity score (AS), 2, 30, 38 and 3 subjects were classified as poor, intermediate, normal, and ultra-rapid metabolizers (PM, IM, NM, UM), respectively. The MR DM/DX phenotypic ratios did not significantly differ between control (no T2D) and T2D groups. The relationship was evaluated between CYP2D6 genotypes grouped by AS and the plasma log(MR DM/DX), urine log(MR DM/DX) and plasma log ratios of the biomarkers. Plasma peaks for m/z 220.1543 and 432.3108 could not be reliably and precisely measured. The marker m/z 597.3382 demonstrated the strongest correlations with both plasma and urine MR DM/DX (rs = 0.71 and 0.65, respectively, p< 0.0001). A significant but lower correlation was observed between the marker m/z 444.3108 and MR DM/DX (rs = 0.42 and 0.39 in plasma and urine, respectively, p< 0.001). There was no correlation between m/z 416.3159 and MR DM/DX. The ROC AUC analysis performed with the m/z 597.3382 marker to determine the cut-off value for discriminating between UM-NM, NM-IM, IM-PM (utilizing the AS) was >0.7.

Conclusion: Magliocco et al. indicated, in their untargeted metabolomic analysis, that the marker m/z 597.3382 showed the best correlation with the reference probe (MR DX/DM). Our exploratory study corroborates that m/z 597.3382 is a promising candidate probe for determining CYP2D6 activity.