Substance-Related DisordersPhase 1NCT00504413
Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone
A Phase 1 study testing midazolam(drug), digoxin (drug), Bupropion (drug) and Methadone (drug) in people with Substance-Related Disorders, run by University of Washington at 1 site in United States.
Trial summary
The purpose of this study is to determine to what extent CYP2B6, CYP3A4, and MDR1 polymorphisms affect the metabolism of methadone. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Substance-Related Disorders
- What is being tested?
- midazolam(drug), digoxin (drug), Bupropion (drug) and Methadone (drug)
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2007to Jan 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy
- Within 25% of ideal body weight
Who cannot join
- Pregnant
- A prisoner
- Enemy, non-combatant
- Smoker
- Have a history of liver disease
- Have a history of heart disease
- Have a history of drug abuse
- Currently on prescription medication
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
University of Washington General Clinical Research Center
Seattle, Washington, 98105
Rheem A Totah, PhD
Danny Shen, PhD
About this study
Official title: Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects
The purpose of this study is to determine to what extent CYP2B6, CYP3A4, and MDR1 polymorphisms affect the metabolism of methadone.
Read the detailed description
Methadone maintenance treatment (MMT) has been used to rehabilitate the opiate addict resulting in a higher quality of life for the patient as well as improving social and psychological functioning while reducing the overall cost to society. The maintenance dose of methadone is highly variable between patients, and drug-drug interactions have been observed between methadone and various medications used to treat a variety of diseases. Identification and understanding of the enzymes responsible for the metabolism of methadone could potentially lead to improved strategy in individualizing methadone dosing and reduce the risk of adverse drug interactions.
Several cytochrome P450 enzymes (CYPs) have been identified and hypothesized to be involved in methadone metabolism in vitro, particularly CYP2B6 and CYP3A4. However, the quantitative contribution of CYP2B6 and CYP3A4 in the elimination clearance of methadone in vivo remains undefined. In addition, methadone is a substrate of the efflux transporter, P-glycoprotein (Pgp) at the intestinal mucosa. We are proposing a pilot study in healthy human subjects to investigate the following hypotheses:
- Pgp limits the gastrointestinal absorption
- Inter-subject variations in CYP2B6 and CYP3A4 activities explain the variation in methadone clearance in vivo
This will be accomplished by correlating the pharmacokinetics of methadone and the phenotype probes for Pgp (digoxin), CYP2B6 (bupropion) and CYP3A4 (midazolam). We plan to use these data to design a human subject study to assess the utility of MDR1 and CYP genotyping in predicting the methadone maintenance dose in a cohort of MMT patients.
- Conditions
- Substance-Related Disorders
- Being tested
- midazolam(drug), digoxin (drug), Bupropion (drug), Methadone (drug)
- Keywords
- Metabolic Networks and Pathways, Methadone, Polymorphism, genetic, Cytochrome P-450 Enzyme System
- Medical subject headings
- Substance-Related Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
midazolam(drug), digoxin (drug)Drug
Midazolam (2mg po) and digoxin (0.5mg po) will be administered one time, an hour apart. Blood concentration will be collected at various points in an 8 hour period.
Bupropion (drug)Drug
Also called Wellbutrin
Bupropion (150mg po) will be administered one time on a separate visit. Blood concentrations will be collected at various points in a 72 hour period.
Methadone (drug)Drug
Methadone (10mg po) will be administered at a separate visit 2 weeks after the bupropion visit. The dose is given once. Blood concentrations will be measured at various points in a 72 hour period. Pupil constriction will be measured and urine will be collected during this period as well.
What is being measured
The primary outcome is the main question the study is designed to answer.
Explore if there is a correlation between the areas of the concentration curves of probe substrates for CYP3A4 and/or CYP2B6 and Pgp and the area of the concentration curve of methadone.
Measured: two years
Secondary outcomes (2)
LC-MS assays will be developed to analyze the plasma content of the probe substrates, methadone and their metabolites. Specifically, midazolam, 1-OH midazolam, bupropion, t-butyl-hydroxy bupropion, digoxin, methadone, and EDDP (a methadone metabolite).
Measured: two years
Isolate and bank the DNA of the subjects for future genotyping of variant alleles that will be identified in this study to be important in methadone pharmacokinetics.
Measured: two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jul 2007 (estimated)
- Study startJul 2007
- Primary completionJan 2011 (estimated)
- Study completionJan 2011 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (63)Papers the sponsor has linked to this study.
- Other trials for Substance-Related DisordersStudies of the same condition, open and under way.
- More trials run by University of WashingtonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Washington
- Sponsor type
- University, hospital or other
- Investigators
- Rheem A Totah, PhD, Principal investigator, University of Washington, Medicinal Chemistry Department
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00504413
- Sponsor's protocol ID
- 30931-A
- Other IDs
- 06-3659-A 01
- Status last verified
- Oct 2010
- First submitted
- 18 Jul 2007
- Last updated
- 13 Oct 2010
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Beckett AH, Taylor JF, Casy AF, Hassan MM. The biotransformation of methadone in man: synthesis and identification of a major metabolite. J Pharm Pharmacol. 1968 Oct;20(10):754-62. doi: 10.1111/j.2042-7158.1968.tb09634.x. No abstract available.
PubMed 4386743Kreek MJ, Vocci FJ. History and current status of opioid maintenance treatments: blending conference session. J Subst Abuse Treat. 2002 Sep;23(2):93-105. doi: 10.1016/s0740-5472(02)00259-3.
PubMed 12220607Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2003;(2):CD002209. doi: 10.1002/14651858.CD002209.
PubMed 12804430Brettle RP. HIV and harm reduction for injection drug users. AIDS. 1991 Feb;5(2):125-36. doi: 10.1097/00002030-199102000-00001. No abstract available.
PubMed 2031687Ward J, Mattrick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, Amsterdam. 1998
Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust. 1999 Feb 1;170(3):104-9. doi: 10.5694/j.1326-5377.1999.tb127675.x.
PubMed 10065120Sorensen JL, Copeland AL. Drug abuse treatment as an HIV prevention strategy: a review. Drug Alcohol Depend. 2000 Apr 1;59(1):17-31. doi: 10.1016/s0376-8716(99)00104-0.
PubMed 10706972Stenbacka M, Leifman A, Romelsjo A. The impact of methadone treatment on registered convictions and arrests in HIV-positive and HIV-negative men and women with one or more treatment periods. Drug Alcohol Rev. 2003 Mar;22(1):27-34. doi: 10.1080/0959523021000059802.
PubMed 12745356Wong KH, Lee SS, Lim WL, Low HK. Adherence to methadone is associated with a lower level of HIV-related risk behaviors in drug users. J Subst Abuse Treat. 2003 Apr;24(3):233-9. doi: 10.1016/s0740-5472(03)00029-1.
PubMed 12810144Bruera E, Kim HN. Cancer pain. JAMA. 2003 Nov 12;290(18):2476-9. doi: 10.1001/jama.290.18.2476. No abstract available.
PubMed 14612485Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986 Jun;25(3):297-312. doi: 10.1016/0304-3959(86)90234-4.
PubMed 3528988Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain. 1997 Mar;70(1):99-101. doi: 10.1016/s0304-3959(96)03313-1.
PubMed 9106815Mercadante S. Methadone in cancer pain. Eur J Pain. 1997;1(2):77-83; discussion 84-5. doi: 10.1016/s1090-3801(97)90064-1.
PubMed 15102407Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol Oncol Clin North Am. 2002 Jun;16(3):543-55. doi: 10.1016/s0889-8588(02)00017-5.
PubMed 12170567Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):PL45-50. doi: 10.1016/0024-3205(94)00426-s.
PubMed 7823756
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects
- ClinicalTrials.gov ID
- NCT00504413
- Acronym / sponsor ID
- 30931-A
- Conditions
- Substance-Related Disorders
- Keywords
- Metabolic Networks and Pathways, Methadone, Polymorphism, genetic, Cytochrome P-450 Enzyme System
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University of WashingtonUniversity, hospital or other
- Study start
- Jul 2007
- Primary completion
- Jan 2011 (estimated)
- Study completion
- Jan 2011 (estimated)
- First posted
- 20 Jul 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine to what extent CYP2B6, CYP3A4, and MDR1 polymorphisms affect the metabolism of methadone.
Detailed description
Methadone maintenance treatment (MMT) has been used to rehabilitate the opiate addict resulting in a higher quality of life for the patient as well as improving social and psychological functioning while reducing the overall cost to society. The maintenance dose of methadone is highly variable between patients, and drug-drug interactions have been observed between methadone and various medications used to treat a variety of diseases. Identification and understanding of the enzymes responsible for the metabolism of methadone could potentially lead to improved strategy in individualizing methadone dosing and reduce the risk of adverse drug interactions.
Several cytochrome P450 enzymes (CYPs) have been identified and hypothesized to be involved in methadone metabolism in vitro, particularly CYP2B6 and CYP3A4. However, the quantitative contribution of CYP2B6 and CYP3A4 in the elimination clearance of methadone in vivo remains undefined. In addition, methadone is a substrate of the efflux transporter, P-glycoprotein (Pgp) at the intestinal mucosa. We are proposing a pilot study in healthy human subjects to investigate the following hypotheses:
- Pgp limits the gastrointestinal absorption
- Inter-subject variations in CYP2B6 and CYP3A4 activities explain the variation in methadone clearance in vivo
This will be accomplished by correlating the pharmacokinetics of methadone and the phenotype probes for Pgp (digoxin), CYP2B6 (bupropion) and CYP3A4 (midazolam). We plan to use these data to design a human subject study to assess the utility of MDR1 and CYP genotyping in predicting the methadone maintenance dose in a cohort of MMT patients.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Healthy
- Within 25% of ideal body weight
Key exclusion criteria (8 listed)
- Pregnant
- A prisoner
- Enemy, non-combatant
- Smoker
- Have a history of liver disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| midazolam(drug), digoxin (drug)Midazolam (2mg po) and digoxin (0.5mg po) will be administered one time, an hour apart. Blood concentration will be collected at various points in an 8 hour period. | Drug | – |
| Bupropion (drug)Also: WellbutrinBupropion (150mg po) will be administered one time on a separate visit. Blood concentrations will be collected at various points in a 72 hour period. | Drug | – |
| Methadone (drug)Methadone (10mg po) will be administered at a separate visit 2 weeks after the bupropion visit. The dose is given once. Blood concentrations will be measured at various points in a 72 hour period. Pupil constriction will be measured and urine will be collected during this period as well. | Drug | – |
Primary outcome
Explore if there is a correlation between the areas of the concentration curves of probe substrates for CYP3A4 and/or CYP2B6 and Pgp and the area of the concentration curve of methadone.
Time frame: two years
2 secondary outcomes
LC-MS assays will be developed to analyze the plasma content of the probe substrates, methadone and their metabolites. Specifically, midazolam, 1-OH midazolam, bupropion, t-butyl-hydroxy bupropion, digoxin, methadone, and EDDP (a methadone metabolite).
Time frame: two years
Isolate and bank the DNA of the subjects for future genotyping of variant alleles that will be identified in this study to be important in methadone pharmacokinetics.
Time frame: two years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Oct 2010.
- Background: PubMed 4386743Beckett AH, Taylor JF, Casy AF, Hassan MM. The biotransformation of methadone in man: synthesis and identification of a major metabolite. J Pharm Pharmacol. 1968 Oct;20(10):754-62. doi: 10.1111/j.2042-7158.1968.tb09634.x. No abstract available.
- Background: PubMed 12220607Kreek MJ, Vocci FJ. History and current status of opioid maintenance treatments: blending conference session. J Subst Abuse Treat. 2002 Sep;23(2):93-105. doi: 10.1016/s0740-5472(02)00259-3.
- Background: PubMed 12804430Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2003;(2):CD002209. doi: 10.1002/14651858.CD002209.
- Background: PubMed 2031687Brettle RP. HIV and harm reduction for injection drug users. AIDS. 1991 Feb;5(2):125-36. doi: 10.1097/00002030-199102000-00001. No abstract available.
- BackgroundWard J, Mattrick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, Amsterdam. 1998
- Background: PubMed 10065120Caplehorn JR, Drummer OH. Mortality associated with New South Wales methadone programs in 1994: lives lost and saved. Med J Aust. 1999 Feb 1;170(3):104-9. doi: 10.5694/j.1326-5377.1999.tb127675.x.
- Background: PubMed 10706972Sorensen JL, Copeland AL. Drug abuse treatment as an HIV prevention strategy: a review. Drug Alcohol Depend. 2000 Apr 1;59(1):17-31. doi: 10.1016/s0376-8716(99)00104-0.
- Background: PubMed 12745356Stenbacka M, Leifman A, Romelsjo A. The impact of methadone treatment on registered convictions and arrests in HIV-positive and HIV-negative men and women with one or more treatment periods. Drug Alcohol Rev. 2003 Mar;22(1):27-34. doi: 10.1080/0959523021000059802.
- Background: PubMed 12810144Wong KH, Lee SS, Lim WL, Low HK. Adherence to methadone is associated with a lower level of HIV-related risk behaviors in drug users. J Subst Abuse Treat. 2003 Apr;24(3):233-9. doi: 10.1016/s0740-5472(03)00029-1.
- Background: PubMed 14612485Bruera E, Kim HN. Cancer pain. JAMA. 2003 Nov 12;290(18):2476-9. doi: 10.1001/jama.290.18.2476. No abstract available.
- Background: PubMed 3528988Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986 Jun;25(3):297-312. doi: 10.1016/0304-3959(86)90234-4.
- Background: PubMed 9106815Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain. 1997 Mar;70(1):99-101. doi: 10.1016/s0304-3959(96)03313-1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rheem A Totah, PhD principal investigator
University of Washington, Medicinal Chemistry Department
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing midazolam(drug), digoxin (drug), Bupropion (drug) and Methadone (drug) in people with Substance-Related Disorders, run by University of Washington at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 Oct 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jean C Dinh, PharmD (206.616.2775, jeandinh@u.washington.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Explore if there is a correlation between the areas of the concentration curves of probe substrates for CYP3A4 and/or CYP2B6 and Pgp and the area of the concentration curve of methadone. (time frame: two years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00504413, which also lists 63 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Oct 2010.