CYP2B6 Polymorphisms in Methadone Disposition

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01648283
• Collaborator: (none)
• Enrollment: 78
• Location: 1
• Arm: 1
• Actual Duration (Months): 30.9
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

This research study will determine if genetic variation in CYP2B6 affects how the body metabolizes methadone.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: IV racemic methadone HCl; Drug: Oral racemic methadone HCl	N/A

Detailed Description

This investigation determined the influence of CYP2B6 genetic variation, specifically CYP2B66 polymorphism, on clinical methadone plasma concentrations, clearance, and metabolism. The hypothesis was that CYP2B66 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 CYP2B61/1, CYP2B61/6 , and CYP2B66/6, and also CYP2B64 and CYP2B65 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Role of CYP2B6 Polymorphisms in Methadone Metabolism and Clearance
• Actual Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methadone arm Intravenous racemic methadone HCl, 6.0 mg bolus Oral deuterated racemic methadone HCl, 11 mg capsule (IND#58,511)	Drug: IV racemic methadone HCl; IV racemic Methadone HC1 6 mg; Drug: Oral racemic methadone HCl; oral d5-methadone HCl 11 mg

Outcome Measures

Primary Outcome Measures

1. Methadone Metabolism [up to 96 hours]

   Plasma metabolite EDDP/methadone area under the concentration-time curve (AUC0-96) ratio

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Each subject must meet all of the following criteria:

• 18-50 yr old

• CYP2B6*1/1, CYP2B61/6 or CYP2B66/*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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University Schoool of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Evan Kharasch, MD, PhD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01648283
• Other Study ID Numbers: 201203105
• First Posted: Jul 24, 2012
• Last Update Posted: Jun 20, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Washington University School of Medicine: methadone polymorphisms
• Additional relevant MeSH terms: Methadone

Study Results

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

Arm/Group Title	Methadone Arm
Arm/Group Description	Intravenous racemic methadone HCl, 6.0 mg bolus 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
Period Title: Overall Study
STARTED	78
COMPLETED	64
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Methadone Arm
Arm/Group Description	Intravenous racemic methadone HCl, 6.0 mg bolus 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
Overall Participants	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	64 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	34 53.1%
Male	30 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.6%
Not Hispanic or Latino	63 98.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	10 15.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 15.6%
White	42 65.6%
More than one race	0 0%
Unknown or Not Reported	2 3.1%
Region of Enrollment (participants) [Number]
United States	64 100%

Outcome Measures

1. Primary Outcome

Title	Methadone Metabolism
Description	Plasma metabolite EDDP/methadone area under the concentration-time curve (AUC0-96) ratio
Time Frame	up to 96 hours

Outcome Measure Data

Analysis Population Description

Plasma EDDP/methadone AUC ratio

Arm/Group Title	CYP2B6*1/*1	CYP2B6*1/*6	CYP2B6*6/*6
Arm/Group Description	Oral R-methadone HCl	Oral R-methadone	Oral R-methadone
Measure Participants	21	20	17
Mean (Standard Deviation) [ratio]	0.082 (0.022)	0.073 (0.026)	0.054 (0.017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

Adverse Events

Arm/Group Title	Methadone Arm
Arm/Group Description	Intravenous racemic methadone HCl, 6.0 mg bolus 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
All Cause Mortality
	Methadone Arm
	Affected / at Risk (%)	# Events
Total	0/67 (0%)
Serious Adverse Events
	Methadone Arm
	Affected / at Risk (%)	# Events
Total	0/67 (0%)
Other (Not Including Serious) Adverse Events
	Methadone Arm
	Affected / at Risk (%)	# Events
Total	56/67 (83.6%)
Gastrointestinal disorders
Nausea	42/67 (62.7%)	42
General disorders
Headache	15/67 (22.4%)	15
Dizzyness	26/67 (38.8%)	26
syncope	1/67 (1.5%)	1
feeling "hyperactive"	1/67 (1.5%)	1
light senstivity	1/67 (1.5%)
Skin and subcutaneous tissue disorders
Itching	26/67 (38.8%)	26

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.