Effect of CYP2B6 Genotype and Efavirenz on the Disposition and Pharmacodynamic of Methadone and Tizanidine in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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).
详细描述
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, CYP2B6*1/*1), intermediate metabolizers (N=20, CYP2B6*1/*6 and *1/*18) and poor metabolizers (N=20, CYP2B6*6/*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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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).
干预措施: Methadone and Tizanidine (Drug)
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
干预措施: Efavirenz, Methadone and Tizanidine (Drug)
结局指标
主要结局
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
时间窗: 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.
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.
次要结局
未报告次要终点
研究者
Zeruesenay Desta
Professor of Medicine
Indiana University