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

标题：阿片类药物和卡博特韦之间的药代动力学、药效学和毒理学相互作用

• 批准号: 10548530
• 负责人: Shilpa J. Buch
• 金额: $ 37.4万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548530
• 关键词: AIDS prevention; Address; Adherence; Anti-Retroviral Agents; Antibodies; Autopsy; Biological Availability; Biological Process; Blood; Blood Chemical Analysis; Blood specimen; Brain; CD34 gene; Clinical; Computer software; Coupled; Data; Dose; Drug Interactions; Drug Kinetics; Drug Regulations; Drug toxicity; Drug user; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Excretory function; Exhibits; Failure; Fatigue; Feces; Female; Glucuronosyltransferase; Goals; Gold; HIV; HIV Infections; Half-Life; Hepatotoxicity; Heroin; Histology; Histones; Illicit Drugs; Imaging Techniques; Immunohistochemistry; Inbred BALB C Mice; Individual; Infection; Inflammatory; Injections; Integrase; Knowledge; Lead; Macaca mulatta; Mass Spectrum Analysis; Measures; Membrane; Metabolism; Modeling; Morphine; Morphology; Mus; Mutation; Naltrexone; Opiate Addiction; Opioid; Opioid Receptor; Oral; Pain; Pain management; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Plasma; Prevention; Property; Prophylactic treatment; Publications; Publishing; Regimen; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Saline; Solubility; Substance Use Disorder; System; Tail; Testing; The Jackson Laboratory; Tissues; Toxic effect; Toxicology; United States; United States Food and Drug Administration; Uridine Diphosphate; Urine; Variant; Viral; Viral Load result; Western Blotting; absorption; antiretroviral therapy; aqueous; attenuation; base; chronic pain; comorbidity; cost effective; drug clearance; drug metabolism; epigenetic variation; experimental study; high risk; humanized mouse; inhibitor; insight; ion mobility; liquid chromatography mass spectrometry; mRNA Expression; male; melting; mouse model; mu opioid receptors; nephrotoxicity; nonhuman primate; novel; opioid abuse; opioid epidemic; opioid exposure; opioid misuse; opioid use disorder; pharmacokinetics and pharmacodynamics; prescription opioid; prescription opioid misuse; response; synergism

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.

摘要声明 我们已经确定了先前被忽视的有关可能的药物相互作用（DDI）的问题 阿片类药物使用障碍（OUDS）患者的艾滋病毒风险很高的患者使用预防性预防（PREP）。 吗啡和cabo​​tegravir被酶，尿苷二磷酸糖糖基转移酶（UGT）代谢 合并后，可以影响药物代谢的速度，从而产生潜在的毒性风险 与合并的艾滋病毒和乌德一起。阿片类药物是疼痛管理的基石，只要它们是 继续为慢性疼痛和/或非法虐待（统一的阿片类药物流行）而被广泛规定 国家（美国）将继续飙升。 Ouds通常与HIV感染合并，研究表明 滥用阿片类镇痛药以及其他非法药物的人很可能很难粘附 致抗逆转录病毒（ART）药物方案。艺术与阿片类药物滥用和/或药物之间的不良DDI 经常报道格德斯。在最近的出版物中，我们证明了与吗啡和艺术的共同曝光 在HIV感染的脑部储层中导致病毒负荷衰减的失败，并增加了病毒的分泌 诱导的炎症分子。与吗啡和ART共同暴露导致几个组蛋白的增加 修饰酶与μ-不同变体的mRNA表达相关的酶 阿片受体；表明表观遗传和阿片类受体的变化可能与调节有关 DDI。知识的差距：对Cabotegravir和吗啡和/或吗啡之间的潜在DDI知之甚少。 治疗阿片类药物使用障碍的药物（Naltrexone）。在这一点上，我们假设当 结合，cabotegravir和吗啡和/或纳曲酮暴露的协同作用，可能影响 药代动力学（PK）和药效学（PD）反应，导致药物毒性。我们进一步选择了 Cabotegravir和阿片类药物的联合暴露导致的表观遗传变异控制PK/PD反应 通过控制药物代谢酶，转运蛋白和/或μ阿片受体。这个新的目标 应用是评估阿片类药物和cabo​​tegravir之间的潜在相互作用。特定目标1将评估 健康小鼠模型中三组药物（cabotegravir-吗啡-Naltrexone）之间的PK反应。 具体目标2将评估三组药物之间的PD反应和毒理学相互作用 在未感染或HIV感染的人源性小鼠模型中。特定目标3将评估PK/PD，并且 非人类隐私中三组药物之间的毒理学相互作用。影响：发现将提供 对Cabotegravir和阿片类药物中不良DDI的潜在机制的新见解 用于临床环境。此外，对药物毛皮物质的理解将确定新目标 这可能有助于干扰阿片类药物和cabo​​tegravir的药代动力学或药效学。