Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir

简要说明 我们已经确定了一个以前被忽视的问题，即可能的药物相互作用（DDI）， 正在使用既存预防（PrEP）的HIV高风险阿片类药物使用障碍（OUD）患者。 吗啡和cabotegravir通过尿苷二磷酸葡萄糖醛酸转移酶（UGT）代谢 当它们结合在一起时，会影响药物代谢的速度，从而对人体产生潜在的毒性风险。 患有艾滋病和口腔溃疡阿片类药物是疼痛管理的基石，只要它们是 继续被广泛用于慢性疼痛和/或滥用药物，阿片类药物在美国的流行， 美国（US）将继续飙升。OUD通常与HIV感染共病，研究表明， 滥用阿片类镇痛药以及其他非法药物的人最有可能难以遵守 抗逆转录病毒（ART）药物治疗方案。ART与阿片类药物滥用和/或药物之间的不良DDI， 经常报告治疗OUD。在最近的一份出版物中，我们表明，同时接触吗啡和ART， 在艾滋病毒感染的大脑水库导致病毒载量的衰减和病毒的分泌增加失败， 诱导炎症分子。吗啡和抗逆转录病毒疗法的共同暴露导致了几种组蛋白的增加， 修饰酶，这些修饰酶与μ- 阿片受体;表明表观遗传和阿片受体的变化可能参与调节 DDI。知识差距：关于cabotegravir和吗啡之间的潜在DDI和/或 治疗阿片类药物使用障碍的药物（纳洛酮）。在这一点上，我们假设， 在组合中，卡替拉韦和吗啡和/或纳洛酮表现出协同作用，其可以影响药物的耐受性。 药物代谢动力学（PK）和药效学（PD）反应，导致药物毒性。我们进一步重申， 卡替拉韦和阿片类药物联合暴露引起的表观遗传变异控制PK/PD反应 通过调节药物代谢酶、转运蛋白和/或μ-阿片受体。这个新的目标 应用的目的是评价阿片类药物和cabotegravir之间的潜在相互作用。具体目标1将评估 三组药物（卡替拉韦-吗啡-纳洛酮）在健康小鼠模型中的PK反应。 具体目标2将评价PD反应和三组药物之间的毒理学相互作用 在未感染或HIV感染的人源化小鼠模型中。具体目标3将评价PK/PD，以及 在非人类灵长类动物中，三组药物之间的毒理学相互作用。影响：调查结果将提供 关于卡替拉韦和阿片类药物不良DDI潜在机制的新见解， 用于临床环境。此外，对药物表观遗传学的理解将确定新的靶点 这可能有助于干扰阿片类药物和cabotegravir的药代动力学或药效学。

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 or pharmacodynamics of opioids and cabotegravir.