Recruiting

Early Phase 1

Efavirenz with Methadone & TizanidineInteraction of CYP2B6 Genotype and Efavirenz With Methadone and Tizanidine PK

Sponsor:

Indiana University

Code:

NCT05789173

Conditions

Drug-Drug Interaction

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Accepted

Interventions

Methadone and Tizanidine

Efavirenz, Methadone and Tizanidine

Study Details

Brief summary:

The main goal of this clinical study is to test how CYP2B6 genetic variations and efavirenz (cornerstone in HIV-1 therapy) dictate the disposition (PK) of CYP2B6 substrate (methadone) and PK and effect (PD) of CYP1A2 substrate (tizanidine). Specifically, the investigators will test whether efavirenz produces CYP2B6 genotype dependent unanticipated DDIs with CYP2B6 (methadone) and CYP1A2 (tizanidine), leading to lack of efficacy or increased toxicity. Healthy volunteers genotyped for CYP2B6\*6 and \*18 alleles will be grouped in to three genotype predicted phenotype groups: 20 normal metabolizer (NM) (CYP2B6\*1/\*1); 20 intermediate metabolizer (IM) (\*1/\*6, or \*1/\*18); and 20 poor metabolizer (PM) (\*6/\*6, \*6/\*18 or \*18/\*18). Each phenotype group will receive methadone and tizanidine (separated by a washout period) on two occasions: at baseline (control) and after treatment with efavirenz (600 mg/day for 17 days).

Conditions

Drug-Drug Interaction

Study ID

NCT05789173

Start date

Oct 6, 2023

Status verified date

Aug, 2026

Completion date

May, 2027

Anticipated

Primary completion date

May, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18 - 65

Healthy Volunteers: Accepted

Inclusion Criteria:

Subjects will be included in the study if participants:

are male and female (approximately 1:1) volunteers between the age of 18 and 65 years old
are judged healthy without any significant medical condition as determined by and decided from a pre-enrollment screening session that include medical history, laboratory tests such as blood and urine tests, vital signs, and an electrical tracing of the heartbeat (electrocardiogram, EKG). The pre-enrollment screening will be done no more than six weeks before the start of the study.
are able and willing to adhere to the study medication restrictions two weeks before initiating the study and during the conduct of the entire study. These will include refraining from taking any prescriptions medications, over-the-counter medications, and herbal, dietary, and alternative supplements that may interact with the metabolism of those study drugs at least 2 weeks prior to the start of the study and until study completion.
are nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at least two weeks prior to and until the completion of the study.
are willing to commit the time requested for this study.

Exclusion Criteria:

Subjects will be excluded from the study if participants:

are underweight (weigh less than 50 kg or 110 lb.) or overweight \[BMI greater than 32\]. Body mass index is calculated using height and weight to estimate how much body fat subjects have.
have laboratory results that do not fall in a healthy range
have an electrical tracing (baseline EKG readings) that are abnormal as decided by the study physician (medical doctor).
have history of intolerance, allergic reactions (e.g., rash) or other forms of hypersensitivities to any of the study medications (efavirenz, tizanidine or methadone).
Have a hemoglobin count below the normal range (male <13.4 gm/dL: and female <12 gm/dL)
have a positive pregnancy urine test (if female) obtained just prior to each study.
are sexually active, who is unable or unwilling to use an appropriate and effective method of birth control (for example barrier methods like diaphragms or condoms) to avoid the possibility of becoming pregnant
are night shift workers in which case taking efavirenz may interfere with their work.
have any significant health condition such heart, liver, or kidney disease
have history or current seizures which may lead to collapse.
have history or current mental illness (brain) such as feeling sad or unhappy, loss of interest in normal activities, worried or suicidality (thoughts about or an unusual preoccupation with ending own life) or suicide attempts.
have gastrointestinal (digestive) disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
have history or current psychiatric disorders such as depression, anxiety, or suicidality or suicide attempts that may be exacerbated by participation in the study
have a history of or current HIV infection or have a lifestyle that places participants at a higher risk for contracting HIV (e.g., drug abuse, excessive alcohol drinking, and having multiple sexual partners).
take more than 2 alcoholic drinks per day on a regular basis for two weeks prior to the study and unwilling to stop alcoholic drinks during the study
unwilling or unable to stop taking drugs of abuse, including tobacco products or marijuana, two weeks prior to and during the entire study period
have a systolic blood pressure lower than 70 mm Hg which may place subjects on high risk for tizanidine induced hypotension
have participated in a research study involving intensive blood sampling or have donated blood within the past two months.
are taking prescription medications, over-the-counter medications, herbal or dietary supplements, and alternative medicines that may interfere with the metabolism of the study drugs (e.g., inhibitors or inducers of CYP2B6 or CYP1A2) and are unable or unwilling to stop taking these medications two weeks prior to and during the entire study period.
are employees or students under supervision of any of the study investigators.
cannot state a good understanding of this study including risks and requirements
are unable to follow the rules of this study.
cannot or unwilling to commit the time requested for this study.

Study Design

Enrollment

60 participants

Anticipated

Allocation

Non randomized

Intervention Model

Sequential

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

experimental: Baseline (control)

Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will receive a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously at baseline (control).

experimental: Efavirenz (treatment)

Each CYP2B6 normal metabolizer (NM) (\*1/\*1), intermediate metabolizer (IM) (\*1/\*6), and poor metabolizer (PM) (\*6/\*6, \*6/\*18, or \*18/\*18) group will be administered a single dose of methadone (10 mg) and a single dose of tizanidine (4 mg) orally simultaneously after 16-day oral treatment with 600 mg/day efavirenz

Interventions

Methadone and Tizanidine

Each CYP2B6 genotype predicted phenotypes will receive methadone (10 mg) and tizanidine (4 mg) by mouth at baseline (control)

Efavirenz, Methadone and Tizanidine

Each CYP2B6 genotype predicted phenotypes will receive methadone (10 mg) and tizanidine (4 mg) by mouth after pretreatment with efavirenz (600 mg PO for 16 days)

Primary outcome measure

Magnitude of effects of CYP2B6 genotype and multiple doses of efavirenz on the: 1) stereoselective disposition of methadone; and 2) disposition and pharmacodynamics of tizanidine [ Time Frame: Methadone and tizanidine plasma concentrations (0-72 hours) will be determined before (control) and after pretreatment with efavirenz (600 mg/day) for 16 days and AUC0-∞ will be estimated. ]

Central Contacts and Locations

Central contacts

Zeruesenay Desta, PhD

3172742823 zdesta@iu.edu

Abi Colwell

317-274-2715 abcolwel@iu.edu

Locations

Indiana University School of Medicine

Recruiting

Indianapolis, Indiana, United States, 46202

Contacts

Zeruesenay Desta, PhD

3172742823 zdesta@iu.edu

Abi Colwell

317-274-2715 abcolwel@iu.edu

More Information

Sponsor

Indiana University

Last update posted

Aug 20, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by Indiana University on 2026-08-20.