Impact of Genetic Polymorphism on Drug-Drug Interactions Involving CYP2D6

Risk of Phenoconversion in Genetic Extensive Metabolizers Healthy Volunteers Carriers of One Fully-Functional and One Non-Functional Allele Versus Carriers of Two Fully-Functional Alleles

CYP2D6 is characterized by a huge variability in the general population, mainly because of genetic polymorphism and drug-drug interactions (DDIs). CYP2D6 genotype is known to have an impact on the extent of DDIs. Indeed several studies have pointed out differential DDIs extent according to CYP2D6 genotype. The terms phenoconversion and phenotype switch are both used to describe the phenomenon by which a given subject changes his phenotype to another due external influence such as DDIs. When given a sufficiently strong CYP2D6 inhibitor, the phenotype of an individual with no mutant allele (extensive metabolizer, EM) of CYP2D6 can be modified to a poor metabolizer (PM) phenotype. This vulnerability is also thought to be dependent on CYP2D6 genotype. Various combinations of alleles predict an EM genotype, which represents about 60 to 70% of the general population. The aim of the study is to determine whether the presence of genetic mutation in CYP2D6 has an impact on DDIs involving the CYP2D6 enzyme. Our interest focuses on CYP2D6 EM carriers of two fully functional alleles and carriers of one non-functional and one functional allele. In order to elucidate this question, CYP2D6 activity will be measured on healthy volunteers by administration of single low doses of dextromethorphan and tramadol in presence or not of duloxetine and paroxetine, two known CYP2D6 inhibitors.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dextromethorphan 5 MG; Drug: Tramadol 10 mg; Drug: Duloxetine 60mg; Drug: Paroxetine 20 mg

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men and women
• Age 18-60 years
• Body Mass Index 18-27
• Understanding of French language and able to give a written inform consent
• CYP2D6 genotype : combination of two fully-functional (normal activity) alleles or of one fully-functional and one non-functional allele (null activity), according to table 1, without gene multiplication

Exclusion Criteria:

• Pregnant or breastfeeding woman
• Any pathologies, use of drugs or food that may affect CYP2D6 activity
• Regular smokers of >5 cigarettes/day
• Renal or hepatic impairment
• Medical history of chronic alcoholism or abuse of psychoactive drugs, including opiate addiction
• Liver transplantation
• Sensitivity to any of the drugs used
• Alteration of hepatic tests more than 2x normal
• Glomerular filtration rate < 60 ml/min/1.73m2

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CYP2D6 gene score 1; carriers of 1 fully functional and 1non functional CYP2D6 alleles	Drug: Dextromethorphan 5 MG; Drug: Tramadol 10 mg; Drug: Duloxetine 60mg; Drug: Paroxetine 20 mg
Experimental: CYP2D6 gene score 2; carriers of 2 fully functional CYP2D6 alleles	Drug: Dextromethorphan 5 MG; Drug: Tramadol 10 mg; Drug: Duloxetine 60mg; Drug: Paroxetine 20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in the proportion of volunteers with urinary metabolic ratio Dextromethorphan/Dextrorphan >0.3	10 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
AUC of plasmatic concentrations probe drugs (dextromethorphan and tramadol) and their metabolites and tramadol) and their metabolites in plasma	24 hours
Cmax of probe drugs (dextromethorphan and tramadol) and their metabolites and tramadol) and their metabolites in plasma and tramadol) and their metabolites in plasma	24 hours
Tmax of plasmatic concentrations probe drugs (dextromethorphan and tramadol) and their metabolites and tramadol) and their metabolites in plasma and tramadol) and their metabolites in plasma	24 hours
Half-life of probe drugs (dextromethorphan and tramadol) and their metabolites and tramadol) and their metabolites in plasma and tramadol) and their metabolites in plasma	24 hours
Clearance of probe drugs (dextromethorphan and tramadol) and their metabolites and tramadol) and their metabolites in plasma	24 hours
Difference in the urinary metabolic ratio tramadol/M1	10 hours

Collaborators and Investigators

• Sponsor: Jules Desmeules
• Investigators: Principal Investigator: Jules A Desmeules, Pr, HUG

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: February 6, 2017
• First Submitted That Met QC Criteria: February 10, 2017
• First Posted (Actual): February 15, 2017

Study Record Updates

• Last Update Posted (Actual): April 19, 2019
• Last Update Submitted That Met QC Criteria: April 18, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Opioid; Narcotics; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Antitussive Agents; Duloxetine Hydrochloride; Paroxetine; Dextromethorphan; Tramadol
• Other Study ID Numbers: 2016-00262