Disulfiram Interactions With HIV Medications: Clinical Implications

说明（由申请人提供）：滥用可卡因和酒精与艾滋病毒感染和传播密切相关。在一些地区，这些药物的滥用在很大程度上助长了这一流行病。虽然有几种药物疗法被批准用于治疗酒精成瘾，但没有一种药物疗法被批准用于治疗可卡因依赖。然而，使用双硫仑（DIS）治疗可卡因或可卡因/酒精使用合并症已经取得了可喜的结果。双硫仑是FDA批准的一种治疗酒精依赖的药物。DIS是醛脱氢酶（ALDH）的抑制剂，据报道，它可以改变肝细胞色素P450酶的功能，这对治疗HIV/AIDS的许多常用药物的代谢至关重要。此外，DIS被cyp3a代谢为其活性代谢物。已知几种抗逆转录病毒（ARV）药物也能改变cyp3a的活性。对于那些可卡因和/或酒精滥用和艾滋病毒疾病的人来说，DIS可能是一种很有希望的治疗方法，但确定和了解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用于临床护理的至关重要的第一步。本项目建议使用标准的临床药理学研究设计，采用受试者内设计来检查DIS（每天62.5 mg或每天250 mg）与常用的HIV治疗药物之间的3种药物相互作用研究，这些药物对CYP 450药物代谢酶系统具有实质性和临床显著的影响，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类逆转录酶抑制剂（NNRTI）和CYP 3A4诱诱剂依非韦伦，以证明给药对ARV药代动力学的影响，以及给药对DIS活性（由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或联合使用对心脏传导、肝功能和血脂影响的临床数据。如果这个项目的结果确定DIS和ARV可以安全地联合使用，DIS将成为那些同时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。开发安全有效的药物治疗艾滋病毒感染者的可卡因和酒精使用障碍，将改善受影响个人的临床过程，同时降低病毒传播的风险。

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.