Population Pharmacokinetics: Methadone-Antiretroviral Interactions in Vietnam

 描述（由申请人提供）：在撒哈拉以南非洲以外地区，大约三分之一的新艾滋病毒感染与注射吸毒有关。由于这一流行病主要是由注射阿片类药物引起的，一些国家已开始将美沙酮维持治疗作为其艾滋病毒预防、治疗和护理战略的一部分。在许多这些环境中，超过30%的接受美沙酮治疗的患者是HIV+。大多数人在接受美沙酮治疗期间的某个时候将接受抗逆转录病毒治疗。世界上最常用的两种ART（奈韦拉平（NVP）和依法韦仑（EFV））与美沙酮之间的相互作用是众所周知的，但在临床人群中的特征很差。这些相互作用经常导致阿片类药物戒断症状、患者不稳定和重新吸毒，导致一系列抗逆转录病毒治疗依从性差和与吸毒相关的发病率增加以及艾滋病毒护理不一致。在美沙酮-ART相互作用的情况下调整美沙酮剂量可以使患者恢复稳定。没有明确的数据来帮助临床医生确定美沙酮-ART相互作用后美沙酮剂量应调整的程度。目前，临床医生必须猜测美沙酮剂量调整，直到达到预期的临床反应。我们工作的总体目标是：以下研究建议的重点是在现实世界的临床环境中建立美沙酮的群体药代动力学模型，其中HIV的流行率较高，并使用NVP和EFV。这将通过两个具体目标来实现：1）在现实世界的临床环境中使用群体药代动力学来测量美沙酮暴露的差异（例如，浓度-时间曲线下面积，AUC;剂量和表观口服清除率之间的关系，CL/F）分别在接受NVP或EFV的患者和未接受NVP或EFV的患者之间;和2）评价选定的遗传多态性对美沙酮药代动力学和美沙酮-NVP和-EFV相互作用的影响。

 DESCRIPTION (provided by applicant): Approximately one in three new HIV infections occurring outside of sub-Saharan Africa is related to injection drug use. Because this epidemic is primarily driven by the injection of opiates, several countries have initiated methadone maintenance treatment as part of their HIV prevention, treatment, and care strategy. In many of these settings more than 30% of patients entering methadone treatment are HIV+. Most will be on antiretroviral therapies (ART) at some point during their treatment with methadone. Interactions between the two most commonly used ART in the world, nevirapine (NVP) and efavirenz (EFV), and methadone are well known but poorly characterized in clinical populations. These interactions frequently lead to opiate withdrawal symptoms, patient destabilization, and return to drug use that results in a cascade of poor ART adherence and increased morbidity related to drug use and inconsistent HIV care. Adjustment of methadone dose in the setting of methadone-ART interactions can return the patient to stability. There are no clear data to help a clinician determine the extent to which a methadone dose should be adjusted following methadone-ART interactions. Currently, clinicians must guess on methadone dose adjustments until the desired clinical response is achieved. The overall goal of our work is to The following research proposal focuses on the creation of a population pharmacokinetic model of methadone in a real-world clinical setting with a high prevalence of HIV and use of NVP and EFV. This will be accomplished through two specific aims: 1) Use population pharmacokinetics in a real-world clinical setting to measure differences in methadone exposure (e.g., area under the concentration-time curve, AUC; and relationship between dose and apparent oral clearance, CL/F) between those on NVP or EFV and those not on NVP or EFV, respectively; and 2) Evaluate the influence of selected genetic polymorphisms on methadone pharmacokinetics and methadone-NVP and -EFV interactions.