Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted with Cobicistat in Healthy Volunteers (R2D2)

每周一次利福喷丁和异烟肼对健康志愿者中用考比司他增强的多替拉韦和达芦那韦稳态药代动力学的影响 (R2D2)

• 批准号: 10471698
• 负责人: Jomy George
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471698
• 关键词: Acquired Immunodeficiency Syndrome; Adherence; Adult; Adverse event; Africa; Anti-Retroviral Agents; Area Under Curve; Asia; Blood; CD4 Positive T Lymphocytes; CYP3A4 gene; Cessation of life; Country; Data; Developing Countries; Diagnosis; Directly Observed Therapy; Disease; Documentation; Dose; Drug Interactions; Drug Kinetics; HIV; HIV Seronegativity; HIV Seropositivity; Half-Life; Incidence; Income; Individual; Infection; Laboratories; Lymphocyte Count; Methods; Morbidity - disease rate; Mycobacterium tuberculosis; Opportunistic Infections; Oral; Participant; Patients; Periodicity; Pharmaceutical Preparations; Phase; Plasma; Population; Protocols documentation; Public Health; Recommendation; Regimen; Reporting; Research Design; Rifabutin; Rifampin; Rifamycins; Risk; Safety; Symptoms; Therapeutic; Time; Translating; Treatment Protocols; Tuberculosis; United States; Viral Load result; Vitamin B6; active method; adherence rate; alternative treatment; antiretroviral therapy; appropriate dose; arm; base; comparative; healthy volunteer; isoniazid; mortality; open label; pathogen; pill; prospective; rifapentine

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. 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, 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 PO 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 months8 and 9 months9 in HIV-infected individuals with LTBI not on antiretroviral therapy (ART), and noninferior to daily INH given for 9 months in both 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 directly observed therapy (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 not currently recommended in HIV-infected adults on ART in the US due to limited data on drug interactions between these agents. Rifamycins can cause significant CYP3A 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 to mitigate these interactions. However, the extent of interaction that may be observed with once weekly RPT is unknown. Darunavir boosted with cobicistat (DRV/c) comprises part of alternative treatment regimens recommended for the treatment of HIV. However, drug interactions between these ARV agents and RPT are of concern. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state PK of DRV/c. This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of DRV/c with coadministration of once weekly RPT and INH given at doses used to treat LTBI. Arm B will be comprised of two phases: (1) DRV/c once daily alone (days 1-4) and (2) DRV/c once daily + (RPT and INH) once weekly (days 5-19). Participants in Arm B will undergo periodic serial ARV PK blood draws on days 4, 14, and 19. DRV/c PK parameters will be determined using non-compartmental methods. Cobicistat levels will only be assessed if DRV concentrations are significantly decreased. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.

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这种病原体。大多数感染者仍处于非活动状态，称为潜伏性结核感染（LTBI），其特点是缺乏症状或感染他人的能力。然而，LTBI 可以重新激活并发展为活动性疾病。结核病对于感染人类免疫缺陷病毒 (HIV) 的个体来说尤其成问题，因为个体发生活动性结核感染的可能性是 HIV 阴性个体的 26 倍，并且随着 CD4 T 淋巴细胞计数下降和病毒载量增加，风险不断增加。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，艾滋病毒阳性者占新发结核病病例的12%。 此外，大约 25% 的结核病死亡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症 (AIDS) 死亡是由结核病造成的。大多数结核病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。尽管如此，结核病仍然构成重大的公共卫生问题。 为了降低 HIV 感染者的发病率和死亡率，对活动性 LTBI 和 LTBI 进行适当的诊断和治疗至关重要。目前，HIV 阳性个体 LTBI 的一线治疗建议包括 (1) 异烟肼 (INH) 每天 300 mg + 吡哆醇 25 mg 每天，持续 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 每天，持续 9 个月。替代治疗方案包括 (1) 利福平 (RIF) 600 mg PO，每日 600 mg，持续 4 个月，或 (2) 利福布丁 (RFB)（根据伴随抗逆转录病毒 (ARV) 药物调整剂量），持续 4 个月。基于 INH 的疗法对于 LTBI 治疗非常有效。然而，由于治疗疗程长和药物负担高，艾滋病毒感染者和未感染者的依从性和治疗完成率都较低。 每周一次的利福喷汀 (RPT) 和 INH 是最近在 HIV LTBI 治疗中添加的另一种选择。研究发现，对于未接受抗逆转录病毒治疗 (ART) 且患有 LTBI 的 HIV 感染者，该方案与每天 300 mg INH 持续 6 个月8 和 9 个月 9 的疗效相似，并且在大部分 HIV 阴性人群中不低于每日 INH 持续 9 个月。 RPT + INH 是 LTBI 的一种有吸引力的治疗选择，因为它在 12 周内每周给药一次，可以作为直接观察疗法 (DOT) 治疗支持的一部分，并且接受该疗法的患者耐受性良好。总的来说，这些优势转化为比 INH 疗法更高的依从率，INH 疗法需要每日给药和 6 至 9 个月的治疗（分别为 82-95% 和 48-85%）。 尽管有这些潜在的好处，但由于这些药物之间药物相互作用的数据有限，目前在美国不建议接受 ART 的 HIV 感染成人使用每周一次的 RPT 联合 INH。每日服用利福霉素可引起显着的 CYP3A 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以减轻这些相互作用。然而，每周一次的 RPT 可能观察到的相互作用程度尚不清楚。 达芦那韦联合考比司他 (DRV/c) 是推荐用于治疗 HIV 的替代治疗方案的一部分。然而，这些抗逆转录病毒药物和 RPT 之间的药物相互作用值得关注。因此，本研究的目的是确定 RPT 和 INH 联合给药对 DRV/c 稳态 PK 的影响。 这是一项开放标签、固定序列、受试者体内药物相互作用研究，旨在评估 DRV/c 与每周一次的 RPT 和 INH 共同给药（以治疗 LTBI 的剂量）的稳态 PK。 B 组将由两个阶段组成：(1) DRV/c 每天一次（第 1-4 天）和 (2) DRV/c 每天一次 +（RPT 和 INH）每周一次（第 5-19 天）。 B 组的参与者将在第 4、14 和 19 天定期进行系列 ARV PK 抽血。 DRV/c PK 参数将使用非房室方法确定。仅当 DRV 浓度显着降低时才会评估考比司他水平。将在各阶段之间比较以下 PK 参数：给药间隔内的曲线下面积、最大血浆浓度、达到最大血浆浓度的时间、终末半衰期、表观口服清除率和最低血浆浓度。不良事件将被分级并记录。