Disulfiram Interactions With HIV Medications: Clinical Implications

描述(申请人提供)：滥用可卡因和酒精与艾滋病毒感染和病毒传播密切相关。在一些地区，这些药物的滥用在很大程度上推动了疫情的蔓延。虽然有几种药物疗法被批准用于酒精成瘾，但还没有药物疗法被批准用于治疗可卡因依赖。然而，FDA批准的治疗酒精依赖的药物双硫兰(DIS)用于治疗可卡因或可卡因/酒精使用障碍，已经取得了令人振奋的结果。DIS是一种乙醛脱氢酶(ALDH)的抑制剂，已被报道改变肝脏细胞色素P450酶的功能，该酶对许多治疗HIV/AIDS的常用药物的代谢至关重要。此外，DIS被CYP 3A代谢成其活性代谢物。几种抗逆转录病毒(ARV)药物也可以改变CyP3A的活性。对于那些有可卡因和/或酒精滥用和HIV疾病的人来说，DIS可能是一种有前途的治疗方法，但识别和了解DIS和ARV之间潜在的药物相互作用的临床相关性是确定这些药物是否可以在临床护理中安全使用的关键的第一步。本项目建议采用标准的临床药理学研究设计，采用受试者内设计，检查DIS(每天62.5毫克或每天250毫克)与经常开出的HIV治疗药物之间的3项药物相互作用研究，这些研究对CYP 450药物代谢酶系统有实质性和临床显著影响，包括蛋白酶抑制剂(PI)和CYP 3A4抑制剂利托那韦和阿扎那韦以及非核苷逆转录酶抑制剂(NNRTI)和CYP 3A4诱导剂efavirenz，以证明DIS对ARV药代动力学的影响以及ARV对DIS活性(由ALDH活性显示)和DIS药代动力学的影响。这些药物单独或联合使用对心脏传导、肝功能和血脂的影响的临床数据也将被获得。如果这个项目的结果确定DIS和ARV可以安全地联合使用，DIS将是那些患有艾滋病毒疾病和可卡因和/或酒精依赖的人的重要药物治疗选择。为艾滋病毒感染者的可卡因和酒精使用障碍开发安全有效的药物疗法将改善受影响个人的临床病程，同时降低病毒传播的风险。 公共卫生相关性：可卡因和酒精滥用与艾滋病毒感染和病毒传播密切相关。双硫兰长期以来一直被美国FDA批准用于治疗酒精中毒，最近的数据显示，它在减少可卡因滥用方面是有效的。双硫兰和抗逆转录病毒药物是由细胞色素P450 3A代谢的，同时使用这些药物可能会产生不良的药物相互作用，这突显了识别和了解这些药物相互作用的临床意义的必要性，以便更有效地治疗同时患有艾滋病毒疾病和可卡因和/或酒精使用障碍的个人。

DESCRIPTION (provided by applicant): The abuse of cocaine and alcohol is strongly linked to HIV infection and transmission of the virus. In some areas, the abuse of these drugs is to a significant degree, driving the epidemic. While several pharmacotherapies are approved for alcohol addiction, no pharmacotherapy has been approved for treatment of cocaine dependence. However, promising results have been obtained with the use of disulfiram (DIS), a FDA approved medication to treat alcohol dependence, for treatment of cocaine or comorbid cocaine/alcohol use disorders. DIS is an inhibitor of aldehyde dehydrogenases (ALDH) and has been reported to alter hepatic cytochrome P450 enzyme function important to metabolism of many drugs frequently used in the treatment of HIV/AIDS. Further, DIS is metabolized to its active metabolite by CYP 3A. Several antiretroviral (ARV) medications are known to alter CYP 3A activity as well. DIS could be a promising treatment for those with cocaine and/or alcohol abuse and HIV disease, but identification and understanding of clinical relevance of potential drug interactions between DIS and ARV are a critically important initial step to determine whether these medications can be used safely in clinical care. This project proposes to use a standard clinical pharmacology study design that employs a within-subject design to examine 3 drug interaction studies between DIS (62.5 mg daily or 250 mg daily) and a frequently prescribed HIV therapeutics that have substantial and clinically significant effects on the CYP 450 drug metabolizing enzyme system including the protease inhibitors (PIs) and CYP 3A4 inhibitors ritonavir and atazanavir and the non-nucleoside reverse transcriptase inhibitor (NNRTI) and CYP 3A4 inducer efavirenz to demonstrate both the effect of DIS administration on ARV pharmacokinetics and the effect of ARV administration on DIS activity (shown by ALDH activity) and DIS pharmacokinetics. Clinical data on effects of these medications alone and in combination on cardiac conduction, hepatic function, and serum lipids will also be obtained. Should results from this project determine that DIS and ARV can be co-administered safely, DIS will be an important pharmacotherapy option for those with comorbid HIV disease and cocaine and/or alcohol dependence. The development of safe and effective pharmacotherapies for cocaine and alcohol use disorders in those with HIV disease will improve the clinical course of affected individuals while decreasing risk of virus transmission. PUBLIC HEALTH RELEVANCE: Cocaine and alcohol abuse are strongly linked to HIV infection and transmission of the virus. Disulfiram has long been approved by the US FDA for treatment of alcoholism and recent data shows it to be effective in reducing cocaine abuse. Disulfiram and antiretroviral medications are metabolized by cytochrome P450 3A and concomitant use of these drugs could potentially produce adverse drug interactions underscoring the need to identify and understand the clinical implications of these drug interactions in order to more effectively treat individuals with both HIV disease and cocaine and/or alcohol use disorders.