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

摘要报表 我们已经发现了一个以前被忽视的问题，即可能存在的药物-药物相互作用(DDI) 使用预先存在的预防措施(PrEP)的阿片类药物使用障碍(OID)患者，艾滋病毒的风险很高。 吗啡和卡替格列韦由尿苷二磷酸葡萄糖醛酸基转移酶(UGT)代谢。 当它们结合在一起时，会影响药物新陈代谢的速度，对人体产生潜在的毒性风险 与艾滋病病毒和OUD并存。阿片类药物是疼痛管理的基石，只要它们是 继续广泛开出治疗慢性疼痛和/或非法滥用的处方，阿片类药物在美国的流行 各州(美国)将继续飙升。ODS通常与艾滋病毒感染并存，研究表明 滥用阿片类镇痛剂以及其他非法药物的个人最有可能难以坚持 抗逆转录病毒(ART)药物治疗方案。ART和阿片类药物滥用和/或药物之间的不良DDI 治疗尿酸尿症的报道很多。在最近的一篇文章中，我们展示了与吗啡和ART的共同暴露 在HIV感染的大脑储存库中，导致病毒负荷减弱失败和病毒分泌增加- 诱导性炎症分子。与吗啡和ART联合暴露导致几种组蛋白的增加- 与μ不同变异体基因表达增加相关的修饰酶- 阿片受体；提示表观遗传和阿片受体的变化可能参与调节 DDI。知识差距：对卡替格列韦、吗啡和/或潜在的DDI知之甚少 治疗阿片类药物使用障碍的药物(纳曲酮)。在这一点上，我们假设当被接受时 卡替格列韦、吗啡和/或纳曲酮的联合应用显示出协同作用，可以影响 药代动力学(PK)和药效学(PD)反应，导致药物毒性。我们进一步假设 卡替格列韦和阿片类药物联合应用引起的表观遗传变异控制PK/PD反应 通过调节药物代谢酶、转运体和/或μ-阿片受体。这项新计划的目标是 应用是评估阿片类药物和卡替格列韦之间的潜在相互作用。特定目标1将评估 卡托维韦-吗啡-纳曲酮三组药物在健康小鼠模型中的PK反应。 特定目标2将评估PD反应，以及三组药物之间的毒理学相互作用 在未感染或感染HIV的人源化小鼠模型中。具体目标3将评估PK/PD，以及 三组药物在非人类灵长类动物中的毒理学相互作用。影响：调查结果将提供 卡替格列韦和阿片类药物不良反应的潜在机制的新见解 在临床环境中使用。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卡替格列韦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.