Impact of Weekly Administration of RPT and INH on TAF Pharmacokinetics in Healthy Volunteers

结核病(TB)是一种由结核分枝杆菌引起的感染，据估计，世界上多达三分之一的人口感染了这种病原体。1大多数感染者仍处于非活动性状态，称为潜伏性结核病感染(LTBI)，其特征是缺乏症状或感染他人的能力。然而，LTBI可以被重新激活并发展为活动性疾病。结核病在感染人类免疫缺陷病毒(HIV)的个人中问题尤其严重，因为个人患活动性结核病感染的可能性是艾滋病毒阴性者的26倍，1随着CD4T淋巴细胞数量下降和病毒载量增加，风险增加。结核病是全球艾滋病毒人群中最常见的机会性感染之一，2014年，艾滋病毒阳性个人占新发结核病病例的12%。此外，约25%的结核病死亡是由感染艾滋病毒的人造成的，33%的艾滋病毒/获得性免疫缺陷综合征(艾滋病)死亡是由结核病引起的。大多数结核病病例和死亡报告发生在非洲和亚洲的发展中国家。收入较高的国家，如美国，发病率要低得多。尽管如此，结核病仍然是一个重大的公共卫生问题。 为了减少HIV感染者的发病率和死亡率，活动性和LTBI的适当诊断和治疗是至关重要的。目前，对艾滋病毒阳性患者的一线治疗建议包括：(1)异烟肼(INH)300毫克/天+吡哆醇25毫克/天，持续9个月；或(2)异烟肼900毫克/周两次(作为直接观察疗法的一部分)+吡哆醇25毫克/天(DOT)，持续9个月。替代治疗方案包括(1)利福平(RIF)600毫克，每天口服一次，为期4个月；或(2)利福平(RFB)(根据伴随的抗逆转录病毒药物调整剂量)，为期4个月。基于异烟肼的疗法对LTBI的治疗非常有效。然而，艾滋病毒感染者和非感染者的依从性和治疗完成率都很低，这是因为疗程长和药片负担高。 利福喷丁(RPT)和异烟肼(INH)每周一次是艾滋病毒LTBI治疗的另一个最近增加的选择。研究发现，在没有接受抗逆转录病毒治疗(ART)的HIV感染者中，这种方案的疗效与在6个月和9个月内每天服用300毫克异烟肼相似，而在大部分HIV阴性的人群中，这种方案的疗效不逊于每天服用9个月的异烟肼。RPT+INH是治疗LTBI的一种有吸引力的治疗选择，因为它在12周内每周服用一次，可以作为DOT治疗支持的一部分给予，并且接受这种疗法的患者耐受性很好。总而言之，这些优势转化为比异烟肼疗法更高的依从率，异烟肼疗法需要每天服药和6-9个月的治疗(分别为82%-95%和48%-85%)。 尽管有这些潜在的好处，但由于缺乏关于这些药物之间相互作用的数据，在美国接受抗逆转录病毒治疗的艾滋病毒感染者中，每周一次的RPT与异烟肼的使用是有限的。每周一次的RPT+异烟肼仅推荐用于接受基于efavirenz(EFV)或raltegravir(Ral)的方案(与阿巴卡韦/拉米夫定或富马酸替诺福韦/恩曲他滨联合使用)的患者。由于利福霉素可在每日给药时引起显著的细胞色素P450同工酶(CYP)3A和P糖蛋白(P-gp)转运蛋白的诱导，RIF或RFB与ARV药物之间的前瞻性药物相互作用研究已告知临床医生是否应避免某些组合或进行适当的剂量调整。然而，每周一次的RPT可能观察到的相互作用的程度是未知的，应该进一步调查。此外，尽管异烟肼未被怀疑与抗逆转录病毒药物有显著的相互作用，但它在调节转运体介导的药物相互作用中的作用尚不清楚，也应进一步研究。 替诺福韦丙氨酰胺(TAF)是目前卫生与公众服务部抗逆转录病毒治疗指南的首选主干药物，是多种推荐的艾滋病毒治疗一线方案的一部分。然而，由于潜在的药物相互作用，不建议将TAF与利福霉素(包括RPT)一起使用。因此，本研究的目的是确定RPT和INH同时给药对血浆TAF、血浆替诺福韦(TFV)和细胞内TFV二磷酸(DP)的稳态药代动力学(PK)的影响。 这是一项开放的、固定序列的受试者内药物相互作用研究，旨在评估TAF、TFV、TFV-DP的稳态PK，并以用于治疗LTBI的剂量每周联合给予一次RPT+INH。该研究将包括两个阶段：(1)单独每天一次的TAF(第1-14天)和(2)每天一次的TAF+基于体重的RPT+每周一次的INH(第15-32天)。参与者将在第14、22和31天进行定期连续ARV PK抽血。 TAF、TFV和TFV-DP PK将使用非隔室方法测定。以下PK参数将在不同阶段进行比较：血浆和PBMC(细胞内)给药间隔的曲线下面积、最大血浆和细胞内浓度、达到最大血浆和细胞内浓度的时间、终端半衰期、表观口服清除量以及最低血浆和细胞内浓度。不良事件将被分级和记录。 在2020年艾滋病毒、肝炎和抗病毒药物临床药理学国际研讨会(10月虚拟会议)上，初步的PK分析被接受用于口头海报演示。

Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, and up to one-third of the worlds population is estimated to be infected with this pathogen.1 The majority of infected individuals remain in an inactive state, referred to as latent TB infection (LTBI), which is characterized by a lack of symptoms or an ability to infect others. However, LTBI can be reactivated and develop into active disease. TB is particularly problematic in individuals infected with human immunodeficiency virus (HIV), as individuals are 26 times more likely to develop active TB infection than HIV-negative individuals,1 with increasing risk as CD4 T lymphocyte counts decline and viral loads increase. TB is one of the most common opportunistic infections in the HIV population worldwide, and in 2014, HIV-positive individuals accounted for 12% of newly developed TB cases. Furthermore, around 25% of all TB deaths were accounted for by those infected with HIV, and 33% of HIV/acquired immunodeficiency syndrome (AIDS) deaths were attributed to TB. The majority of TB cases and deaths are reported in developing countries in Africa and Asia. Higher-income countries, such as the United States, are associated with much lower incidence rates. Nevertheless, TB still poses a significant public health problem. In order to reduce the morbidity and mortality observed in individuals with HIV, appropriate diagnosis and treatment of active and LTBI is essential. Currently, the first-line treatment recommendations for LTBI in HIV-positive individuals include (1) isoniazid (INH) 300 mg daily + pyridoxine 25 mg daily for 9 months or (2) INH 900 mg twice weekly (as part of directly observed therapy DOT) + pyridoxine 25 mg daily for 9 months. Alternative treatment options include (1) rifampin (RIF) 600 mg given orally once daily for 4 months, or (2) rifabutin (RFB) (dose-adjusted for concomitant antiretroviral ARV drugs) for 4 months. INH-based therapies are highly effective for LTBI treatment. However, adherence and treatment completion is low in both HIV-infected and uninfected individuals due to long treatment courses and high pill burden. Once weekly rifapentine (RPT) and INH is another more recently added option to available LTBI treatments in HIV. This regimen was found to be similar in efficacy to INH 300 mg daily for 6 months and 9 months9 in HIV-infected individuals with LTBI not on antiretroviral therapy (ART), and noninferior to daily INH given for 9 months in a largely HIV-negative population. RPT + INH is an attractive therapeutic option for LTBI as it is dosed once weekly over 12 weeks, can be given as part of DOT treatment support, and is well tolerated by patients receiving this therapy. Collectively, these advantages translate into higher rates of adherence comparatively to INH therapy, which requires daily dosing and 6 to 9 months of therapy (82%-95% vs. 48%-85%, respectively). Despite these potential benefits, the use of once weekly RPT with INH is limited in HIV-infected adults on ART in the US due to the lack of data on drug interactions between these agents. Once-weekly RPT + INH is only recommended in patients receiving efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine). As rifamycins can cause significant cytochrome P450 isozyme (CYP) 3A and P glycoprotein (P-gp) transporter induction with daily administration, prospective drug interaction studies between RIF or RFB and ARV agents have informed clinicians of whether to avoid certain combinations or make appropriate dose adjustments. However, the extent of interaction that may be observed with once weekly RPT is unknown and should be further investigated. Furthermore, although INH is not suspected to interact significantly with ARVs, its role in modulating transporter-mediated drug interactions is unknown and should also be further investigated. Tenofovir alafenamide (TAF) is a preferred backbone agent by the current Department of Health and Human Services ARV guidelines and is a part of multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular TFV diphosphate (dp). This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of TAF, TFV, TFV-dp with coadministration of once weekly RPT +INH given at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily alone (days 1-14) and (2) TAF once daily + weight based RPT + INH once weekly (days 15-32). Participants will undergo periodic serial ARV PK blood draws on days 14, 22, and 31. TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following PK parameters will be compared between phases: area under the curve over the dosing interval in plasma and PBMCs (intracellular), maximum plasma and intracellular concentrations, time to maximum plasma and intracellular concentrations, terminal half-life, apparent oral clearance, and minimum plasma and intracellular concentrations. Adverse events will be graded and recorded. A preliminary PK analysis was accepted for oral poster presentation at the 2020 International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Antiviral Drugs (October Virtual Meeting).