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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.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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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.

Jean C Dinh, PharmD contact

206.616.2775

jeandinh@u.washington.edu

Rheem A Totah, PhD contact

206.543.9481

rtotah@u.washington.edu

United States1 site, 1 recruiting

  • University of Washington General Clinical Research Center

    Seattle, Washington, 98105

    Rheem A Totah, PhD

    Danny Shen, PhD

    Recruiting

Other trials in United States

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:

  1. Pgp limits the gastrointestinal absorption
  2. 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.

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.

  1. 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)

  1. 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

  2. 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.

  1. First posted20 Jul 2007 (estimated)
  2. Study startJul 2007
  3. Primary completionJan 2011 (estimated)
  4. Study completionJan 2011 (estimated)

Resources

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)
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 4386743

  • Kreek 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 12220607

  • Mattick 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 12804430

  • Brettle 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 2031687

  • Ward 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 10065120

  • Sorensen 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 10706972

  • Stenbacka 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 12745356

  • Wong 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 12810144

  • Bruera E, Kim HN. Cancer pain. JAMA. 2003 Nov 12;290(18):2476-9. doi: 10.1001/jama.290.18.2476. No abstract available.

    PubMed 14612485

  • Gourlay 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 3528988

  • Manfredi 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 9106815

  • Mercadante 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 15102407

  • Ripamonti 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 12170567

  • Kristensen 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

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.

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