Clinical Trial to Evaluate Pharmacological Interactions Between γ-hydroxybutyrate (GHB) and Cobicistat
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- concentration in plasma of GHB
研究概览
简要总结
Gamma-hydroxybutyric acid (GHB) is a popular "party drug" because it is inexpensive and easy to ingest. The calming and euphoric effects of GHB in low doses have given the drug the nickname "liquid ecstasy". However, at doses >60 mg/kg coma, convulsions, and respiratory depression can occur. If the drug combinates with alcohol these effects intensify, especially respiratory depression and hypotension.
Lately a phenomenon called Chemsex has been spreading across big European cities. This is a form of recreational drug use and it is believed that can be, in part, the cause of the increasing in consumption of GHB. Chemsex is especially common among men who have sex with other men (MSM) and in people living with HIV, with up to 50% of HIV-positive MSM reporting to be engaged in chemsex in recent months. This population is specially concerning since the combination of ART with the drug can cause pharmacological interactions leading to overdose.
Specifically, this study intends to evaluate the drug interaction with low doses of cobicistat, an antiretroviral drug enhancer, since there are two case reports of life-threatening overdoses in patients on treatment with high doses of another enhancer that has a similar effect than cobicistat, but there are no studies about interactions with low doses.
详细描述
Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in most mammalian tissues at nanomolar concentrations and a minor metabolite or precursor of gammaaminobutyric acid (GABA). GHB was first synthesized in 1960 by the French biochemist H.-M. Laborit who was searching for analogues of GABA. Currently, medically formulated GHB sodium oxybate (Xyrem®) is approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and cataplexy associated with narcolepsy.
Pharmacokinetics of GHB are characterized by rapid oral absorption, with peak concentrations in plasma 20-45 min after dosing, and half-life of 20-30 min. The majority of the dose is eliminated completely within 4-8 h. Metabolism of GHB occurs via GHB dehydrogenase, which transforms it into succinic semialdehyde and, by a second oxidation step with transformation into succinic acid, it is then ultimately metabolized to water and excreted through breath as carbon dioxide. However, GHB exposure is increased in patients with liver function impairment and has been suggested presystemic (hepatic first pass) metabolism mediated by the CYP450 system in humans.
During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. During the last years, GHB has become a major concern in emergency rooms of some countries due to an important increase in the number of cases of intoxications.
Since the drug is both inexpensive and easy to ingest, it has been popular as a "party drug." The calming and euphoric effects of GHB in low doses (20-30 mg/kg) have given the drug the nickname "liquid ecstasy". At higher doses (> 50 mg/kg), the hypnotic effects are more prominent and at doses >60 mg/kg coma, convulsions, and respiratory depression can occur. The clinical hallmark of GHB poisoning is rapid onset of coma, with respiratory depression, hypoventilation and bradycardia. Combination with alcohol potentiates these effects, especially respiratory depression and hypotension.
Regular use of GHB is thought to be relatively higher in the lesbian, gay, bisexual, and transgender community. Anecdotal evidence suggests that GHB use is increasing and this may be driven in part by an increase in the incidence of chemsex. Chemsex is a specific form of recreational drug use involving specific drugs such as GHB/γ-butyrolactone (GBL), methylamphetamine and mephedrone, alone or in combination, to enhance or prolong sexual sessions. Such sessions can last for several days, involve multiple partners and include high risk behaviour.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Males and females* aging 18-45 years.
- •Body weight ranging between 50 and 100 Kg.
- •Previous experience with the consumption of sedatives (alcohol, cannabis, benzodiazepines, GHB or other hypnotics).
- •Absence of abnormalities in the screening ECG and blood/urine tests.
- •Agree with the study procedures and signature of the informed consent.
- •Women of childbearing potential must have a negative pregnancy test prior to randomization into the study and commitment to use at least one of these birth control methods: male or female condom with or without spermicide, cap, diaphragm or sponge with or without spermicide, intrauterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence during the study. Condom use is considered as an additional method of contraception only and cannot be the only method of contraception used as not been considered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines.
- •Based on ICH, M3 (R2) 2009 a woman is considered of childbearing potential: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include tubal ligation, hysterectomy, bilateral oophorectomy.
排除标准
- •Prior history of medical or psychiatric adverse reaction following GHB consumption.
- •Current substance use disorder (DSM-V, dependence, addiction) of any drug or substance of abuse.
- •Prior history of substance use disorder (DSM-V, drug use disorder or addiction) of any drug or substance of abuse (except nicotine).
- •Smokers>10 cigarettes/day.
- •History of any physical condition or major surgery within the previous three months.
- •History of individual psychiatric conditions or schizophrenia in first-degree relatives.
- •History of gastrointestinal, hepatic, renal diseases or other conditions which, in opinion of the investigator, may affect drug absorption, distribution, metabolism or elimination.
- •Alcohol intake higher than 4 units/day (40 g) in men or 2 units/day (20 g) in women.
- •Positive urine drug test (Amphetamines, Barbiturates, Benzodiazepines, Cocaine, MDMA, Methamphetamine, Morphine/Opioids, Methadone, tricyclic antidepressants, THC)
- •HIV infection, chronic hepatitis C (IgG VHC) or B (HBsAg).
- •Lactose intolerance
- •Pregnancy, lactation, or planned pregnancy during the study period.
- •Current or recent pharmacological treatment (≥3 doses per week) in the last 2 weeks
- •Blood donation in the 3 previous months
- •Participation in another clinical trial in the previous 3 months
研究组 & 干预措施
COBI period (5 days) + Placebo period (5 days)
volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB
干预措施: Cobicistat 150 MG (Drug)
COBI period (5 days) + Placebo period (5 days)
volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB
干预措施: Placebo (Drug)
COBI period (5 days) + Placebo period (5 days)
volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB
干预措施: GHB (Drug)
Placebo period (5 days) + COBI period (5 days)
volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB.
干预措施: Cobicistat 150 MG (Drug)
Placebo period (5 days) + COBI period (5 days)
volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB.
干预措施: Placebo (Drug)
Placebo period (5 days) + COBI period (5 days)
volunteers will receive once-daily placebo for 5 days. On day 5, participants will receive a single oral dose of GHB. After a washout period for 7 days, volunteers will receive once daily cobicistat for 5 days. On day 5, participants will receive a single oral dose of GHB.
干预措施: GHB (Drug)
结局指标
主要结局
concentration in plasma of GHB
时间窗: days 5 and 17
mg/dl
Proportion of participants reporting adverse events.
时间窗: Since baseline to day 28
% of participants developing related adverse events.
次要结局
- subjective effects of GHB -ARCI(days 5 and 17)
- physiological effects: heart rate(days 5 and 17)
- physiological effects: blood pressure(days 5 and 17)
- physiological effects : oxygen saturation(days 5 and 17)
- subjective effects of GHB - Visual analog scale(days 5 and 17)