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

结核病（TB）是由结核分枝杆菌引起的感染，估计世界上多达三分之一的人口感染了这种病原体。1大多数感染者处于非活动状态，称为潜伏性结核感染（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成活动性疾病。结核病在感染人类免疫缺陷病毒（HIV）的个体中尤其成问题，因为个体发生活动性结核病感染的可能性是HIV阴性个体的26倍，1随着CD 4 T淋巴细胞计数下降和病毒载量增加，风险增加。结核病是全球艾滋病毒感染人群中最常见的机会性感染之一，2014年，艾滋病毒阳性个体占新发结核病病例的12%。此外，所有结核病死亡中约25%是由艾滋病毒感染者造成的，33%的艾滋病毒/获得性免疫缺陷综合征（艾滋病）死亡归因于结核病。报告的大多数结核病例和死亡发生在非洲和亚洲的发展中国家。美国等高收入国家的发病率要低得多。然而，结核病仍然是一个严重的公共卫生问题。 为了降低艾滋病毒感染者的发病率和死亡率，对活动性和LTBI进行适当的诊断和治疗至关重要。目前，HIV阳性个体中LTBI的一线治疗建议包括（1）异烟肼（INH）300 mg每日+吡哆醇25 mg每日9个月或（2）INH 900 mg每周两次（作为直接观察治疗DOT的一部分）+吡哆醇25 mg每日9个月。替代治疗选择包括（1）利福平（RIF）600 mg，口服，每日一次，持续4个月，或（2）利福必利（RFB）（针对伴随使用的抗逆转录病毒ARV药物进行剂量调整），持续4个月。基于INH的疗法对于LTBI治疗非常有效。然而，由于疗程长和药丸负担高，艾滋病毒感染者和未感染者的依从性和治疗完成率都很低。 每周一次利福喷丁（RPT）和INH是另一个最近增加的选择，以提供LTBI治疗艾滋病毒。在未接受抗逆转录病毒治疗（ART）的HIV感染LTBI患者中，该方案的疗效与INH 300 mg/d持续6个月和9个月9相似，并且在大部分HIV阴性人群中不劣于INH每日给药9个月。RPT + INH是LTBI的一种有吸引力的治疗选择，因为它每周给药一次，持续12周，可以作为DOT治疗支持的一部分，并且接受这种治疗的患者耐受性良好。总的来说，这些优势转化为与INH治疗相比更高的依从性，INH治疗需要每日给药和6至9个月的治疗（分别为82%-95%和48%-85%）。 尽管有这些潜在的益处，但在美国，由于缺乏这些药物之间药物相互作用的数据，每周一次RPT与INH的使用在接受ART的HIV感染成人中受到限制。每周一次的RPT + INH仅推荐给接受基于依法韦仑（EFV）或雷特格韦（RAL）的方案（与阿巴卡韦/拉米夫定或富马酸替诺福韦酯/恩曲他滨联合）的患者。由于利福霉素可引起显著的细胞色素P450同工酶（CYP 3A）和 每日给药的P糖蛋白（P-gp）转运蛋白诱导，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RPT可能观察到的相互作用程度尚不清楚，应进一步研究。此外，虽然INH不被怀疑与抗逆转录病毒药物显着相互作用，其在调节转运介导的药物相互作用的作用是未知的，也应该进一步研究。 替诺福韦艾拉酚胺（TAF）是目前卫生与公众服务部ARV指南的首选骨干药物，也是治疗HIV的多个推荐一线方案的一部分。然而，由于潜在的药物相互作用，不建议TAF与利福霉素（包括RPT）联合使用。因此，本研究的目的是确定伴随RPT和INH给药对血浆TAF、血浆替诺福韦（TFV）和细胞内TFV二磷酸盐（dp）的稳态药代动力学（PK）的影响。 这是一项开放标签、固定序列、受试者内药物相互作用研究，旨在评价TAF、TFV、TFV-dp与每周一次RPT +INH联合给药（以治疗LTBI的剂量给药）的稳态PK。研究将包括两个阶段：（1）TAF每日一次单独给药（第1-14天）和（2）TAF每日一次+基于体重的RPT + INH每周一次给药（第15-32天）。受试者将在第14、22和31天接受定期系列ARV PK采血。 将使用非房室方法确定TAF、TFV和TFV-dp PK。将比较两个阶段之间的以下PK参数：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、至最大血浆和细胞内浓度的时间、终末半衰期、表观口服清除率以及最小血浆和细胞内浓度。将对不良事件进行分级和记录。

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.