Healthy Volunteers
Conditions
Keywords
methadone polymorphisms
Brief summary
This research study will determine if genetic variation in CYP2B6 affects how the body metabolizes methadone.
Detailed description
This investigation determined the influence of CYP2B6 genetic variation, specifically CYP2B6\*6 polymorphism, on clinical methadone plasma concentrations, clearance, and metabolism. The hypothesis was that CYP2B6\*6 heterozygotes or homozygotes would have reduced metabolism and clearance. A secondary objective was to evaluate other less common genotypic variants, when encountered. Healthy volunteers in genotype cohorts CYP2B6\*1/\*1, CYP2B6\*1/\*6 , and CYP2B6\*6/\*6, and also CYP2B6\*4 and CYP2B6\*5 carriers, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry. The primary outcome measure was methadone metabolism, measured as plasma metabolite/patent area under the concentration-time curve ratio and metabolite formation clearance.
Interventions
DRUGIV racemic methadone HCl
IV racemic Methadone HC1 6 mg
DRUGOral racemic methadone HCl
oral d5-methadone HCl 11 mg
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Each subject must meet all of the following criteria: * 18-50 yr old * CYP2B6\*1/\*1, CYP2B6\*1/\*6 or CYP2B6\*6/\*6 genotype * Good general health with no remarkable medical conditions * BMI \< 33 * Provided informed consent
Exclusion criteria
Subjects will not be enrolled if any of the following criteria exist: * Known history of liver or kidney disease * Use of prescription or non prescription medications, herbals or foods known to be metabolized by or affect CYP2B6 * Females who are pregnant or nursing * Known history of drug or alcohol addiction (prior or present addiction or treatment for addiction) * Direct physical access to and routine handling of addicting drugs in the regular course of duty (this is a routine exclusion from studies of drugs with addiction potential)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Methadone Metabolism | up to 96 hours | Plasma metabolite EDDP/methadone area under the concentration-time curve (AUC0-96) ratio |
Countries
United States
Participant flow
Recruitment details
11 subject withdrawals following consent due to personal reasons and/or conflicts, 3 subjects not evaluable, 64 subjects evaluable and included in analysis
Participants by arm
| Arm | Count |
|---|---|
| Methadone Arm 1. Intravenous racemic methadone HCl, 6.0 mg bolus
2. Oral deuterated racemic methadone HCl, 11 mg capsule (IND#58,511) CYP2B6 is phenotyped by the clearance oral racemic bupropion 150mg
racemic methadone HC1: IV racemic Methadone HC1 6 mg oral d5-methadon HC1 11 mg
Oral deuterated racemic methadone HCl,: 11 mg capsule once | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Methadone Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Region of Enrollment United States | 64 participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 67 |
| other Total, other adverse events | 56 / 67 |
| serious Total, serious adverse events | 0 / 67 |
Outcome results
Primary
Methadone Metabolism
Plasma metabolite EDDP/methadone area under the concentration-time curve (AUC0-96) ratio
Time frame: up to 96 hours
Population: Plasma EDDP/methadone AUC ratio
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CYP2B6*1/*1 | Methadone Metabolism | 0.082 ratio | Standard Deviation 0.022 |
| CYP2B6*1/*6 | Methadone Metabolism | 0.073 ratio | Standard Deviation 0.026 |
| CYP2B6*6/*6 | Methadone Metabolism | 0.054 ratio | Standard Deviation 0.017 |
p-value: <0.05ANOVA