SUMMARY STATEMENT We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP). Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT) and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral- induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone- modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ- opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model. Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets that might help in the interference with pharmacokinetics o...