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.

概要声明 我们发现了一个以前被忽视的问题，即可能存在的药物间相互作用 (DDI) 患有阿片类药物使用障碍 (OUD) 且艾滋病毒高风险且正在使用预先存在的预防 (PrEP) 的患者。 吗啡和卡博特韦通过尿苷二磷酸葡萄糖醛酸转移酶 (UGT) 代谢 当两者结合时，会影响药物代谢速率，从而对人体产生潜在的毒性风险 患有 HIV 和 OUD 共病。阿片类药物是疼痛管理的基石，只要它们 继续广泛用于治疗慢性疼痛和/或非法滥用，阿片类药物在美国流行 各州（美国）将继续飙升。 OUD 常常与 HIV 感染并存，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坚持 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 治疗 OUD 的情况经常被报道。在最近的一篇出版物中，我们证明了吗啡和 ART 的共同暴露 在艾滋病毒感染的脑储存库中，病毒载量减弱失败，病毒分泌增加。 诱导炎症分子。与吗啡和 ART 共同暴露会导致几种组蛋白的增加 与μ-不同变体的mRNA表达增加相关的修饰酶 阿片受体；表明表观遗传和阿片受体的变化可能参与调节 直拨。知识差距：对于卡博特韦和吗啡和/或之间潜在的 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，我们假设当考虑到 卡博特韦和吗啡和/或纳曲酮的组合表现出协同作用，可以影响 药代动力学（PK）和药效（PD）反应，导致药物毒性。我们进一步假设 卡博特韦和阿片类药物联合暴露导致的表观遗传变异控制着 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 该应用的目的是评估阿片类药物和卡博特韦之间的潜在相互作用。具体目标 1 将评估 三组药物（卡博替拉韦 - 吗啡 - 纳曲酮）在健康小鼠模型中的 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 在未感染或感染 HIV 的人源化小鼠模型中。具体目标 3 将评估 PK/PD，并且 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 关于卡博特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卡博特韦的药代动力学或药效学。