Disulfiram Interactions With HIV Medications: Clinical Implications

描述（由申请人提供）：可卡因和酒精的滥用与艾滋病毒感染和病毒传播密切相关。在某些地区，滥用这些药物在很大程度上推动了这一流行病。虽然有几种药物疗法被批准用于酒精成瘾，但没有药物疗法被批准用于治疗可卡因依赖。然而，使用双硫仑（DIS）（FDA批准的治疗酒精依赖的药物）治疗可卡因或共病可卡因/酒精使用障碍已获得了有希望的结果。DIS是醛脱氢酶（ALDH）的抑制剂，并且已报道改变肝细胞色素P450酶功能，所述酶功能对于经常用于治疗HIV/AIDS的许多药物的代谢是重要的。此外，DIS被β 3A代谢成其活性代谢物。已知几种抗逆转录病毒（ARV）药物也会改变α 3A的活性。DIS可能是可卡因和/或酒精滥用和艾滋病患者的一种有希望的治疗方法，但识别和理解DIS和ARV之间潜在药物相互作用的临床相关性是确定这些药物是否可以安全地用于临床护理的至关重要的初始步骤。本项目建议使用标准临床药理学研究设计，采用受试者内设计，检查DIS之间的3项药物相互作用研究（每日62.5 mg或每日250 mg）和经常处方的HIV治疗剂，对包括蛋白酶抑制剂（PI）在内的HIV 450药物代谢酶系统具有实质性和临床显著影响和抗逆转录酶3A 4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）和抗逆转录酶3A 4诱导剂依法韦仑，以证明DIS给药对ARV药代动力学的影响以及ARV给药对DIS活性（通过ALDH活性显示）和DIS药代动力学的影响。还将获得这些药物单独使用和联合使用对心脏传导、肝功能和血脂影响的临床数据。如果该项目的结果确定DIS和ARV可以安全地联合给药，DIS将成为艾滋病毒疾病和可卡因和/或酒精依赖共病患者的重要药物治疗选择。开发治疗艾滋病毒感染者可卡因和酒精使用障碍的安全有效的药物疗法，将改善受影响者的临床病程，同时降低病毒传播的风险。 公共卫生相关性：吸毒和酗酒与艾滋病毒感染和病毒传播密切相关。双硫仑长期以来一直被美国FDA批准用于治疗酒精中毒，最近的数据显示它可以有效减少可卡因滥用。双硫仑和抗逆转录病毒药物通过细胞色素P450 3A代谢，合并使用这些药物可能会产生不良药物相互作用，强调需要识别和了解这些药物相互作用的临床意义，以便更有效地治疗HIV疾病和可卡因和/或酒精使用障碍患者。

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.