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

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.