Interaction of CYP2B6 Genotype and Efavirenz with Methadone and Tizanidine PK

Phase

Condition

N/A

Treatment

Efavirenz, Methadone and Tizanidine

Methadone and Tizanidine

Clinical Study ID

NCT05789173

17726

R35GM145383

Ages 18-65
All Genders
Accepts Healthy Volunteers

Study 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) (CYP2B61/*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).

Eligibility Criteria

Inclusion

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 65years old
are judged healthy without any significant medical condition as determined by anddecided from a pre-enrollment screening session that include medical history,laboratory tests such as blood and urine tests, vital signs, and an electricaltracing of the heartbeat (electrocardiogram, EKG). The pre-enrollment screening willbe 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 beforeinitiating the study and during the conduct of the entire study. These will includerefraining from taking any prescriptions medications, over-the-counter medications,and herbal, dietary, and alternative supplements that may interact with themetabolism of those study drugs at least 2 weeks prior to the start of the study anduntil study completion.
are nonsmoker or individuals willing to refrain from smoking or use of tobacco ormarijuana 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

Exclusion Criteria:

Subjects will be excluded from the study if participants:
are underweight (weigh less than 50 kg or 110 lb.) or overweight [BMI greaterthan 32]. Body mass index is calculated using height and weight to estimate howmuch 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 decidedby the study physician (medical doctor).
have history of intolerance, allergic reactions (e.g., rash) or other forms ofhypersensitivities to any of the study medications (efavirenz, tizanidine ormethadone).
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 eachstudy.
are sexually active, who is unable or unwilling to use an appropriate andeffective method of birth control (for example barrier methods like diaphragmsor condoms) to avoid the possibility of becoming pregnant
are night shift workers in which case taking efavirenz may interfere with theirwork.
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 aboutor an unusual preoccupation with ending own life) or suicide attempts.
have gastrointestinal (digestive) disorders such as persistent diarrhea ormalabsorption that would interfere with the absorption of orally administereddrugs.
have history or current psychiatric disorders such as depression, anxiety, orsuicidality or suicide attempts that may be exacerbated by participation in thestudy
have a history of or current HIV infection or have a lifestyle that placesparticipants at a higher risk for contracting HIV (e.g., drug abuse, excessivealcohol drinking, and having multiple sexual partners).
take more than 2 alcoholic drinks per day on a regular basis for two weeksprior to the study and unwilling to stop alcoholic drinks during the study
unwilling or unable to stop taking drugs of abuse, including tobacco productsor 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 onhigh risk for tizanidine induced hypotension
have participated in a research study involving intensive blood sampling orhave donated blood within the past two months.
are taking prescription medications, over-the-counter medications, herbal ordietary supplements, and alternative medicines that may interfere with themetabolism of the study drugs (e.g., inhibitors or inducers of CYP2B6 orCYP1A2) and are unable or unwilling to stop taking these medications two weeksprior 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 andrequirements
are unable to follow the rules of this study.
cannot or unwilling to commit the time requested for this study.

Study Design

Efavirenz, Methadone and Tizanidine

October 06, 2023

April 15, 2026

Study Description

This is an open-label, two period, fixed sequence study in healthy volunteers genotyped for CYP2B6 allele (*6 and 18) investigating the metabolism, pharmacokinetics (PK) and pharmacodynamics (PD) of a single oral dose of tizanidine and methadone before and after oral pre-treatment with 600 mg/day efavirenz for 16 days. Enrollment targets will be normal metabolizers (N=20, CYP2B61/1), intermediate metabolizers (N=20, CYP2B61/*6 and *1/18) and poor metabolizers (N=20, CYP2B66/*6; *18/*18, and *6/*18).

Schedule of assessment:

A. PHASE 1 (CONTROL PHASE): Tizanidine and methadone pharmacokinetics and pharmacodynamics will be determined at baseline.

Day 1 (1st inpatient ICRC overnight stay).

Eligible volunteers who fulfill all inclusion and exclusion criteria will be requested to arrive in the morning (about 7 am) at ICRC on the first study day (Day 1) after an overnight fasting. On the evening prior to the inpatient ICRC study day (day 1), it is important that subjects have nothing to eat or drink after 11 pm except for water. If a female volunteer, a urine pregnancy test will be performed. This test must be negative (not pregnant) to take part in the study. A sterile indwelling intravenous catheter (small, flexible, plastic tube) will be inserted in a vein in one arm for blood collection. A physician will be available for consultation. Pre-dose (baseline) blood (about 7 mL blood or about 1.5 teaspoons) and urine samples, vital sign such as blood pressure (systolic and diastolic blood pressure and heart/pulse rate), respiration rate, oral temperature, breathing rate, and EKG recordings will be obtained.

Subjects will then receive a single dose of tizanidine (4 mg) and a single dose of methadone (10 mg) on empty stomach by mouth with 250 ml drinking water. Blood samples (~7 ml) will be drawn into EDTA-containing tubes at 20 and 40 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours after tizanidine and methadone administration while at the ICRC. To measure tizanidine pharmacodynamic effects, blood pressure (systolic and diastolic blood pressure and heart rate) will be measured twice from the forearm of the subjects in a sitting position with blood pressure monitor immediately after each blood sample. EKG will be monitored at 1, 2, 4, 6, 8, 10, 12 and 24 hours after tizanidine and methadone administration. All urine voided during the 24 hours after drug administration will be collected in two fractions in urine jugs (0 to 12 hours and 12 to 24 hours); all of urine voided 0-12 hours in one container and all urine voided 12-24 hours in the other container. Plasma will be separated by centrifugation within 30 minutes. Urine volume in each fraction will be recorded and two 10-ml aliquots each will be retained from each fraction. Plasma and urine aliquots will be stored at -80°C until analysis. Subjects will receive a standard breakfast 2 hours and lunch 4 hours after methadone and tizanidine administration, and free access to food and water thereafter. Subjects will be requested to report immediately of any unusual feelings.

Day 2 (inpatient ICRC):

After the 24-hour blood and urine sampling and measurements of EKG, blood pressure and vital signs (Day 2), the intravenous catheter (small, flexible, plastic tube) will be removed, and then subjects will be discharged from the ICRC inpatient clinic with the advice to comeback to ICRC outpatient clinic on the mornings of Day 3 and Day 4.

Day 3 (outpatient visit):

In the morning of Day 3 (48 hour) after tizanidine and methadone administration, subjects will come to the ICRC for a short visit (approximately 30 min) to draw blood (about 7 ml or 1.5 teaspoons) by direct needle puncture of a vein in one of the arms.

Day 4 (outpatient visit):

In the morning of Day 4 (72 hour) after tizanidine and methadone administration, subjects will come to the ICRC for a short visit (approximately 30 min) to draw blood (about 7 ml or 1.5 teaspoons) by direct needle puncture of a vein in one of the arms.

After the blood draw on Day 4, subjects will be given the following to take home:

a supply of the study medication, efavirenz, for subjects to start taking at home starting that evening and continue for 16 consecutive days (600 mg/day) per instructed.
a diary will be given to subjects to take home to record the time subjects took efavirenz every evening and any side effects participants may experience.

B. PHASE 2 (EFAVIRENZ TREATMENT PHASE)

Day 4 to day 19 (home):

After the 72-hour blood draw for period 1 (Day 4), subjects will be given a supply of efavirenz to take home. Starting day 4, subjects will be requested to take 600 mg efavirenz orally once a day every evening 2 hours before or 2 hours after a dinner for 16 consecutive days (Day 4 to Day 19). It is important that volunteers take the study medication approximately the same time on each evening. Taking efavirenz during the evening is required to reduce efavirenz-mediated CNS adverse effects. Since efavirenz has a long half-life (∼76 hours after single dose and∼50 at steady state), a total of 16 days of efavirenz treatment is required to achieve steady-state plasma concentrations of efavirenz and near steady-state autoinduction of metabolism. In the event subjects miss a dose it is very important that participants contact the research coordinator for further instructions. In addition, subjects will receive a diary to record the time of the medication was taken and to record CNS symptoms, and any other feelings or side effects experienced during the study. The subjects will be requested to adhere to dietary restrictions throughout the study. Minor rescheduling (+/- 2 days) of the subject's fixed inpatient/outpatient visits are allowed including adjusting the amount of study medication (up to 2 doses less or up to 2 doses more) to be given prior to the subject's second inpatient visit.

C. PHASE 3 (STEADY STATE PHASE). In phase 3, tizanidine and methadone pharmacokinetics and pharmacodynamics will be determined after chronic dosing with efavirenz 600 mg/day for 16 days).

Day 20 (second inpatient ICRC overnight stay):

On Day 20 (Inpatient stay), subjects will be requested to arrive at the ICRC inpatient at about 7 am after overnight fasting. After 11 pm the night before admission to the ICRC, subjects will be requested not to eat anything except water. A urine pregnancy test (if female) will be obtained, and the urine pregnancy test must be negative. Then, a sterile indwelling intravenous catheter will be inserted in one arm for blood collection. Pre-dose (baseline) blood and urine samples, vital sign such as blood pressure (systolic and diastolic blood pressure and heart/pulse rate), respiration rate, oral temperature, breathing rate, and EKG recordings will be obtained. Then, subjects will receive efavirenz (600 mg PO) with tizanidine (4 mg by mouth) and methadone (10 mg) in the morning with 250 ml water. All other subsequent procedures including tizanidine and methadone plasma and urine sampling, pharmacokinetics and pharmacodynamics determinations will be made exactly as described in PHASE 1 (Day 1). The same samples collected will also be used to quantify efavirenz and metabolites. Subjects will receive a standard breakfast 2 hours and lunch 4 hours after methadone and tizanidine administration, and free access to food and water thereafter.

Day 21 (inpatient ICRC):

After the 24-hour blood and urine sampling and measurements of EKG, blood pressure and vital signs (Day 21), the intravenous catheter (small, flexible, plastic tube) will be removed, and then subjects will be discharged from the ICRC inpatient clinic with the advice to comeback to ICRC outpatient clinic on the mornings of Day 22 and Day 23.

Day 22 (outpatient visit):

In the morning of Day 22 (48 hour) after tizanidine and methadone administration, subjects will come to the ICRC for a short visit (approximately 30 min) to draw blood (about 7 ml or 1.5 teaspoons) by direct needle puncture of a vein in one of the arms.

Day 23 (outpatient visit):

In the mornings of Day 23 (72 hour) after tizanidine and methadone administration, subjects will come to the ICRC for a short visit (approximately 30 min) to draw blood (about 7 ml or 1.5 teaspoons) by direct needle puncture of a vein in one of the arms. On Day 23, subjects will be requested to bring the bottle containing home medications either empty or with any leftover efavirenz pills as well as study diary with participants. Day 23, after the 72-hour blood draw, marks the end of the entire study and subjects will be discharged home. Day 23 will mark the completion of the entire study and subjects will be discharged from the study after the 72-hour blood sample and health assessment.

Connect with a study center

Indiana University School of Medicine
Indianapolis, Indiana 46202
United States
Active - Recruiting
Zeruesenay Desta
Indianapolis, Indiana 46202
United States
Site Not Available

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