The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers
Condition: Opiod Use Disorder
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Opioids are medicines that control pain. But they are often misused, which can lead to
      illness and death. Opioids increase dopamine to the brain, which makes people feel good and
      often causes them to crave drugs, leading to misuse and addiction. An investigational drug
      ANS-6637 may lower the dopamine surge and stop opioid craving. Midazolam is a drug approved
      for anxiety. Researchers want to give the two drugs together and see if ANS-6637 affects
      midazolam levels, to help understand how ANS-6637 is used in the body.

      Objective:

      To study the safety, tolerability, and effects of ANS-6637 taken with and without midazolam.

      Eligibility:

      Healthy adults 18 65 years old

      Design:

      Participants will be screened with a medical history, physical exam, and blood and heart
      tests. Participants who can get pregnant will have a pregnancy test.

      Participants must agree to use 2 types of birth control during the study, if applicable.

      Participants will stay at the clinic for 10 days. Meals will be provided. Participants will
      not be allowed to:

      Leave NIH campus

      Eat or drink anything with caffeine, alcohol, or certain juices

      Use any nicotine or related products (including vaping)

      Use any medicines (including herbal)

      During the clinic stay, participants will:

      Fast overnight several times

      Have blood drawn most days. Twice, a small tube will be inserted in an arm vein for frequent
      blood samples.

      Repeat screening tests and answer questions about their mood several times

      Get midazolam syrup in water on 1 day

      Take 6 ANS-6637 tablets by mouth on 5 days

      Take both study drugs on 1 day

      A few days later, participants will have a follow-up visit to repeat screening tests and
      answer questions about their mood.
    

Detailed description: 
      Opioid use causes a myriad of effects which contribute to significant morbidity and early
      mortality, and is associated with risky sexual behavior and injection drug use (IDU), two
      major forms of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) transmission in
      urban and suburban United States. Through these high-risk behaviors, persons with opioid use
      disorder (OUD) develop both direct comorbidities (e.g. blood stream infections and infectious
      endocarditis), as well as risk-associated illnesses (e.g. sexually transmitted infections,
      HCV and hepatitis B virus [HBV]) which have considerable downstream health care effects. As
      such, there is a need for pharmacologic agents in the treatment of OUD that go beyond
      avoidance of withdrawal and facilitate decreased frequency or complete cessation of opioid
      use.

      The biologic mechanism of OUD, common to all forms of addiction, is a conditioned drug
      cue-related response in the CNS, causing a dopamine surge. If effective, a central
      pharmacologic strategy targeting the aberrant reward circuitry seen in OUD could potentially
      reduce drug craving and result in opioid abstinence.

      In the SEARCH Pharmacokinetic (PK) investigation, we aim to understand the pharmacokinetic
      signal of the novel, oral agent ANS-6637, an aldehyde dehydrogenase 2 (ALDH-2) inhibitor that
      has the potential to reduce dopamine surge in the CNS and inhibit opioid craving. In
      preclinical studies, the active metabolite of ANS-6637, GS-548351, showed substrate dependent
      inhibition of CYP3A in vitro, with little or no inhibitory effect on the activities of other
      cytochrome P450 (CYP) enzymes. As such, the current investigation seeks to explore the
      potential inhibition of CYP3A by ANS-6637 with the FDA-recommended CYP3A probe substrate,
      midazolam.
    

Intervention name(s): ANS-6637
Intervention type(s): Drug
Intervention description(s): Subjects will receive (1) midazolam 5 mg po single dose on Day 1 followed by (2) Drug free period on Day 2 followed by (3) ANS-6637 600 mg po daily (Days 3-7) to reach steady state followed by (4) ANS-6637 600 mg po single dose + midazolam 5mg po single dose on Day 8
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Reward Pathway; Pharmacokinetics; Dopamine; Opioid Use; Addiction