Interaction of CYP2B6 Genotype and Efavirenz With Methadone and Tizanidine PK

NCT05789173 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: 17726R35GM145383
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• 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

  1. The primary PK interaction magnitude with R- and S-methadone will be quantified using the treatment:control \[+efavirenz:-efavirenz (baseline)\] ratios of the area under the time concentration curve to infinity (AUC0-∞) of S- and R-methadone. 2. The primary PK interaction magnitude with tizanidine will be quantified using the treatment:control \[+efavirenz:-efavirenz (baseline)\] ratios of the area under the time concentration curve to infinity (AUC0-∞) of tizanidine.

  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.

Study Arms (2)

Baseline (control)

EXPERIMENTAL

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).

Drug: Methadone and Tizanidine

Efavirenz (treatment)

EXPERIMENTAL

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

Drug: Efavirenz, Methadone and Tizanidine

Interventions

Methadone and Tizanidine DRUG

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

Baseline (control)

Efavirenz, Methadone and Tizanidine DRUG

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)

Efavirenz (treatment)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: Male and Female (1:1)
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Indiana University: lead
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (1)

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

RECRUITING

MeSH Terms

Interventions

Methadone; tizanidine; efavirenz

Intervention Hierarchy (Ancestors)

Ketones; Organic Chemicals

Central Study Contacts

Zeruesenay Desta, PhD

CONTACT

3172742823; zdesta@iu.edu

Abi Colwell

CONTACT

317-274-2715; abcolwel@iu.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Open-label, two period, fixed sequence clinical study

Study Record Dates

• First Submitted: March 3, 2023
• First Posted: March 29, 2023
• Study Start: October 6, 2023
• Primary Completion: April 15, 2026
• Study Completion: April 15, 2026
• Last Updated: February 12, 2026

Record last verified: 2026-02

Locations

US (1)