Pharmacokinetics and Pharmacodynamics of Dolutegravir in Children Weighing ≥20 Kg Living with HIV with and without TB Coinfection

多替拉韦在体重≤20公斤的HIV感染者合并或未合并结核感染的儿童中的药代动力学和药效学

• 批准号: 10175510
• 负责人: Awewura Jacob Kwara
• 金额: $ 17.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175510
• 关键词: 15 year old; ABCB1 gene; ABCG2 gene; Acquired Immunodeficiency Syndrome; Address; Adolescent; Adult; Adverse event; Africa; African; Age; Anti-Retroviral Agents; Antitubercular Agents; Biological; CYP3A4 gene; Cessation of life; Child; Childhood; Clinical Trials; Data; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Drug resistance; Enzyme Induction; Film; Formulation; Frequencies; Fumarates; Generations; Genes; Genetic; Genetic Variation; Ghana; Goals; Guidelines; HIV; HIV drug resistance; HIV therapy; HIV/TB; Individual; Infection; Integrase; Investigation; Lamivudine; Life; Malnutrition; Medical; Minor; Morbidity - disease rate; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Population; Recommendation; Regimen; Reporting; Research; Research Priority; Rifampin; Safety; Tablets; Tenofovir; Time; Treatment Protocols; Tuberculosis; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; United States; United States Food and Drug Administration; United States National Institutes of Health; Update; Virus Diseases; Weighing patient; World Health Organization; absorption; age effect; antiretroviral therapy; co-infection; comorbidity; design; dosage; experience; gene interaction; inhibitor/antagonist; innovation; mortality; neuropsychiatry; next generation; novel; pharmacokinetics and pharmacodynamics; treatment guidelines; tuberculosis treatment

ABSTRACT Children and adolescents living with human immunodeficiency virus (HIV) infection are a distinct key population from adults who have not fully benefited from the recent advances in antiretroviral therapy (ART) because of lack of age-appropriate drug formulations as well as relevant research that informs dosing recommendations for the newer antiretrovirals. Dolutegravir (DTG) is a novel second-generation integrase strand transfer inhibitor (INSTI) that is highly efficacious, safer and easy to use with a higher genetic barrier to the emergence of HIV drug resistance. The World Health Organization (WHO) updated guidelines in 2019 recommend DTG-containing regimens as preferred for the treatment of HIV in adults, adolescents and children weighing ≥20 kg. In Africa, DTG is available as the fixed-dose combination (FDC) tenofovir disoproxil fumarate (TDF) 300 mg/lamivudine (3TC) 300 mg/DTG 50 mg (TLD) and standalone 50 mg tablet. Thus, TLD is the only formulation that will be prescribed to children in the African region despite lack of supportive evidence from clinical trials or pharmacokinetics/pharmacodynamics (PK/PD) studies that it will be safe and effective. While it is expected that TLD will to be efficacious in children, verification that it achieves desired PK and safety profile in children is important. A second issue is that tuberculosis (TB) is a common comorbidity of HIV in Africa. Double dose DTG is also recommended for TB/HIV coinfection in children weighing ≥20 kg. To date, DTG 50 mg twice a day has not been studied in children with TB/HIV coinfection on rifampin-containing TB therapy. Dolutegravir is primarily metabolized by UDP-glucuronosyltransferase 1A1 (UGT1A1) with minor contribution (~10%) from cytochrome P450 3A4 (CYP3A4). Genetic variations in UGT1A1, ABCG2 and NR1I2 genes has been identified as significant covariates of DTG PK. Not only is DTG susceptible to potential drug-drug interactions due to enzyme induction, there may be additional variability due to effects of genetic and biologic covariates such as age, malnutrition and comorbidities that influence drug absorption in children in Africa. In this exploratory R21, we propose to rapidly examine the PK and safety of DTG in eligible children and adolescents as the drug is rolled out in Ghana. Our primary goal is to determine the PK and safety of DTG in children weighing ≥20 kg living with HIV with or without TB coinfection. In aim 1, we will evaluate the PK and safety of dolutegravir in ARV-naïve and ARV-experienced children and adolescents living with HIV who are prescribed TLD. In aim 2, we will evaluate the PK and safety of DTG 50 mg twice a day during rifampin- containing anti-tuberculosis therapy compared to 50 mg a day after stopping anti-Tb treatment in children and adolescents with TB/HIV coinfection. Successful completion of these aims will provide timely evidence for rational use DTG in children. The proposed studies are not only significant and innovative, they address NIH priorities of implementation of next generation HIV therapies with better safety and ease of use in a key population and challenges of HIV-associated TB coinfection therapy.

抽象的 感染人类免疫缺陷病毒 (HIV) 的儿童和青少年是一个明显的关键 尚未完全受益于抗逆转录病毒治疗 (ART) 最新进展的成年人群体 由于缺乏适合年龄的药物配方以及指导剂量的相关研究 对新型抗逆转录病毒药物的建议 Dolutegravir (DTG) 是一种新型的第二代整合酶。 链转移抑制剂（INSTI），高效、安全、易于使用，具有更高的遗传屏障 世界卫生组织 (WHO) 于 2019 年更新了指南。 建议将含有 DTG 的治疗方案作为成人、青少年和儿童 HIV 治疗的首选方案 在非洲，DTG 可作为固定剂量组合 (FDC) 富马酸替诺福韦二吡呋酯使用。 (TDF) 300 mg/拉米夫定 (3TC) 300 mg/DTG 50 mg (TLD) 和单独的 50 mg 片剂 因此，TLD 是唯一的片剂。 尽管缺乏支持证据，但仍将向非洲地区的儿童开具处方 临床试验或药代动力学/药效学（PK/PD）研究表明它是安全有效的。 预计 TLD 对儿童有效，验证其达到预期的 PK 和安全性 第二个问题是结核病 (TB) 是非洲艾滋病毒的常见合并症。 对于体重 ≥ 20 公斤的儿童，也建议使用双剂量 DTG。迄今为止，DTG 50。 尚未对接受含利福平结核病治疗的结核病/艾滋病毒合并感染儿童进行研究，每天两次。 多替拉韦主要由 UDP-葡萄糖醛酸基转移酶 1A1 (UGT1A1) 代谢，贡献较小 (~10%) 来自细胞色素 P450 3A4 (CYP3A4) UGT1A1、ABCG2 和 NR1I2 基因的遗传变异。 被确定为 DTG PK 的重要协变量，DTG 不仅容易受到潜在药物-药物的影响。 由于酶诱导而产生的相互作用，由于遗传和生物的影响，可能存在额外的变异性 年龄、营养不良和合并症等影响非洲儿童药物吸收的协变量。 在这个探索性 R21 中，我们建议快速检查 DTG 在符合条件的儿童中的 PK 和安全性，以及 该药物在加纳推出时，我们的主要目标是确定 DTG 在青少年中的 PK 和安全性。 体重 ≥20 公斤的 HIV 感染儿童，无论是否合并感染结核病，在目标 1 中，我们将评估 PK 和 多替拉韦对于未接受过抗逆转录病毒治疗和经历过抗逆转录病毒治疗的艾滋病毒感染儿童和青少年的安全性 在目标 2 中，我们将评估利福平治疗期间每天两次 DTG 50 mg 的 PK 和安全性。 儿童和儿童停止抗结核治疗后每天服用 50 毫克抗结核药物 结核病/艾滋病毒双重感染的青少年的成功完成将为我们提供及时的证据。 在儿童中合理使用 DTG 所提出的研究不仅具有重要意义和创新性，而且还针对 NIH。 实施下一代艾滋病毒疗法的优先事项，在关键方面具有更好的安全性和易用性 人群和艾滋病毒相关结核病合并感染治疗的挑战。