Endobiotics for Phenotyping of Human Cytochrome P450 Enzymes (ENDOCYP2D6)

Endobiotics for Phenotyping of Human Cytochrome P450 Enzymes: Use of Metabolomics for the Identification of New CYP2D6 Endogenous Biomarkers in Healthy Volunteers

CYP2D6 metabolizes ~25% of all marketed drugs. There is an important variability in the activity of this enzyme among individuals. The cause of this variability might be environmental, genetic, ethnical or even related to a disease. The administration of a CYP2D6 probe drug (e.g. dextromethorphan) is a good way to characterize CYP2D6 phenotype. Nonetheless, it is relatively invasive and the vulnerable population (e.g. pregnant women) cannot be phenotyped in this manner. Therefore, finding an endogenous substance which is metabolized by CYP2D6 could replace usual phenotyping procedure using a probe drug. This study evaluates the impact of a CYP2D6 inhibitor and of genetic polymorphism on the metabolome of healthy volunteers in order to identify new CYP2D6 biomarkers. To this end, untargeted metabolomics analysis using LC-HRMS will be performed on plasma and urine samples This single-centre open-label clinical trial will include 40 healthy subjects (men and women) between 18 and 65 years. Eligible participants will be assigned to a study group according to their CYP2D6 genotypes: poor metabolizers (PMs) and extensive/ultrarapid metabolizers (EMs-UMs). Two sessions will take place for each subjects.

Session 1: CYP2D6 phenotyping (dextromethorphan 5 mg, single dose) Session 2: idem session 1 with prior uptake of a CYP2D6 inhibitor (paroxetine 10 or 20 mg, one dose a day for 7 days).

In both sessions, urine will be collected up to 24 hours and capillary/venous blood will be sampled before phenotyping for metabolomics analyses. Urine will also be collected for 4 hours after dextromethorphan intake in order to phenotype the CYP2D6 enzyme.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dextromethorphan 5 MG; Drug: Paroxetine 10Mg Tablet; Drug: Paroxetine 20Mg Tablet

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland
    • HUG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men and women
• Age 18-65 years
• Body Mass Index (BMI) 18-27
• Understanding of French language and able to give a written inform consent
• CYP2D6 genotype : activity score = 0 (PMs) or activity score ≥ 1 (EMs-UMs)
• Reliable contraception during the whole study, including a barrier method

Exclusion Criteria:

• Participation in any other interventional clinical study within 3 months prior to inclusion
• Pregnant or breastfeeding woman
• Any pathologies, use of drugs or food that may affect CYP activity (based on the 'drug interactions and cytochromes P450' table published by the Service of Clinical Pharmacology and Toxicology, HUG54 and on the investigator's knowledge)
• Regular smokers of ≥ 10 cigarettes/day
• Alcohol intake 2 days prior to session 1 and during paroxetine intake
• Medical history of chronic alcoholism or abuse of psychoactive drugs
• Regular use of psychotropic substances
• Sensitivity to any of the drugs used
• Alteration of hepatic tests (ASAT, ALAT, BILI, GGT) more than 3x normal
• Psychiatric disorders
• Beck Score ≥10 (question related to suicide >0)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYP2D6 gene score 0; CYP2D6 gene score 0: carrier of two non-functional alleles	Drug: Dextromethorphan 5 MG; dextromethorphan 5 mg po; Drug: Paroxetine 10Mg Tablet; Paroxetine 10 mg po
Experimental: CYP2D6 gene score ≥1; CYP2D6 gene score ≥1: carrier of one fully-functional and one non-functional allele of CYP2D6 , one fully-functional and one reduced-function of CYP2D6, two fully-functional alleles of CYP2D6 or more than two functional alleles alleles	Drug: Dextromethorphan 5 MG; dextromethorphan 5 mg po; Drug: Paroxetine 20Mg Tablet; Paroxetine 20 mg po

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify endogenous markers of CYP2D6 activity in urine and plasma using untargeted metabolomics	Metabolomic strategie (LC-Q-Exactive HRMS) will be used to identify and characterize endogenous compounds that correlate with the urinary metabolic ratio dextromethorphan/dextrorphan before and after administration of paroxetine, a strong CYP2D6 inhibitor.	7 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference in DEM/DOR urinary ratio before and after administration of paroxetine	7 days
Correlation of significant ions with DEM/DOR urinary ratio or CYP2D6 activity score	7 days

Collaborators and Investigators

• Sponsor: Jules Desmeules

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): July 31, 2019
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: April 18, 2019
• First Submitted That Met QC Criteria: December 4, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Actual): January 4, 2022
• Last Update Submitted That Met QC Criteria: January 3, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Antitussive Agents; Paroxetine; Dextromethorphan
• Other Study ID Numbers: 2018-01637

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No