Clinical Trial to Evaluate Pharmacological Interactions Between γ-hydroxybutyrate (GHB) and Cobicistat
Condition: Pharmacokinetic Interactions; HIV
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.

      Although the phenomenon of chemsex was initially limited to the metropolitan area of London,
      it is getting spread across other big European cities, making of this an emerging global
      health issue. Chemsex is especially common among men who have sex with other men (MSM) and in
      people living with HIV (PLWH), with up to 50% of HIV-positive MSM reporting to be engaged in
      chemsex in recent months.

      Consumption of recreational drugs in PLWH has been associated with high-risk practices for
      sexually transmitted diseases. In addition, use of drugs in patients taking antiretroviral
      therapy (ART) might result in pharmacological interactions with potential risk of overdosing.
      Noteworthy, widespread use of chemsex drugs has resulted in increased rates of overdose and
      associated deaths, and Handley & Flanagan have reported an increase in the number of cases of
      fatal poisoning with GHB, mephedrone and ketamine in England and Wales since 2008. Also,
      GHB-associated deaths have been reported from the USA, Canada, Europe and Australia.

      Cobicistat (GS-9350) is a pharmacokinetic enhancer that was developed to inhibit CYP3A
      activity in a time- and concentration-dependent manner, thus boosting other antiretroviral
      drugs. Results from clinical trials showed that it can increase the plasma exposure of
      elvitegravir, atazanavir, and darunavir. Similarly, cobicistat increases the exposure to many
      other xenobiotics. For example, it is well known that CYP3A4 inhibition leads to a
      significant increase in concentrations of sildenafil and other erectile dysfunction agents,
      and that a dose adjustment is needed in this scenario. Similarly, CYP3A4 inhibition increased
      ketamine exposure in a small clinical trial in healthy volunteers.

      There are two case reports in the literature of well documented life-threatening overdoses on
      GHB and MDMA in HIV-positive patients on treatment with high-doses of ritonavir (600 mg bid).
      However, the possibility for this drug interaction with the low doses of pharmacoenhancers
      currently used (ritonavir 100 mg qd, cobicistat 150 mg qd) is still a matter for debate,
      Despite data suggesting the possibility of drug interactions between cobicistat and GHB,
      formal pharmacokinetic studies assessing this issue are lacking.
    

Intervention name(s): Cobicistat 150 MG; Placebo; GHB
Intervention type(s): Drug; Drug; Drug
Intervention description(s): once daily cobicistat (150 mg QD) for 5 days; once daily lactose capsules (as aspect cobicistat capsules); single oral dose of GHB (25 mg/kg) on days 5 and 17
Other intervention name(s): Cobicistat; XYREM
Intervention MeSH terms: Cobicistat
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Participants will undergo two 5-day treatment periods (COBI and placebo) separated by a 7-day washout period:
COBI period: volunteers will receive once daily cobicistat (150 mg QD) for 5 days.
Placebo period: volunteers will receive once-daily placebo (lactose) for 5 days. On day 5 of each treatment period, participants will receive a single oral dose of GHB (25 mg/kg).
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: pharmacokinetic interactions; chemsex; GHB; cobicistat; γ-hydroxybutyrate