The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers

Phase 1

Completed

Conditions: Opiod Use Disorder

Interventions: Drug: ANS-6637

Registration Number: NCT03831971

Lead Sponsor: National Institutes of Health Clinical Center (CC)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ANS-6637 & Midazolam	ANS-6637	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

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics - Time to Maximum Concentration of Midazolam Alone	Day 1	Time to maximum plasma concentration (tmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Time to Maximum Concentration of 1-hydroxymidazolam Alone	Day 1	Time to maximum plasma concentration (tmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Maximum Total Plasma Concentration of Midazolam Alone	Day 1	Maximum total plasma concentration (Cmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Maximum Total Plasma Concentration of 1-hydroxymidazolam Alone	Day 1	Maximum total plasma concentration (Cmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Plasma Exposure of Midazolam Alone	Day 1	Midazolam plasma area under the concentration time curve 0-infinity. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Plasma Exposure of 1-hydroxymidazolam Alone	Day 1	1-hydroxymidazolam plasma area under the concentration time curve (time 0-infinity). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Elimination of Midazolam Alone	Day 1	Half-life. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Elimination of 1-hydroxymidazolam Alone	Day 1	Half-life. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Time to Maximum Concentration of Midazolam: Midazolam Plus Steady State ANS-6637	Day 8	Time to maximum plasma concentration (tmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Time to Maximum Concentration of 1-hydroxymidazolam: Midazolam Plus Steady State ANS-6637	Day 8	Time to maximum plasma concentration (tmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Maximum Total Plasma Concentration of Midazolam: Midazolam Plus Steady State ANS-6637	Day 8	Maximum total plasma concentration (Cmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Maximum Total Plasma Concentration of 1-hydroxymidazolam: Midazolam Plus Steady State ANS-6637	Day 8	Maximum total plasma concentration (Cmax). The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Plasma Exposure of Midazolam: Midazolam Plus Steady State ANS-6637	Day 8	Midazolam plasma area under the concentration time curve 0-infinity. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Plasma Exposure of 1-hydroxymidazolam: Midazolam Plus Steady State ANS-6637	Day 8	1-hydroxymidazolam plasma area under the concentration time curve 0-infinity. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Elimination of Midazolam: Midazolam Plus Steady State ANS-6637	Day 8	Half-life. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.
Pharmacokinetics - Elimination of 1-hydroxymidazolam: Midazolam Plus Steady State ANS-6637	Day 8	Half-life. The summary PK results were informed by a continuous measurement at the following serial blood collection time points: 0 (pre-dose), then 0.5, 1, 2, 3, 4, 6, 8, 12, 22, and 24 hours postdose.