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: 10311554
• 负责人: Awewura Jacob Kwara
• 金额: $ 20.64万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311554
• 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; 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.

摘要 感染人类免疫缺陷病毒（艾滋病毒）的儿童和青少年是一个独特的关键 未充分受益于抗逆转录病毒疗法（ART）最新进展的成年人 由于缺乏适合年龄的药物配方以及相关研究， 新的抗逆转录病毒药物的建议。度鲁特韦（DTG）是一种新型的第二代整合酶 链转移抑制剂（CITI）是一种高效、安全和易于使用的药物，具有较高的遗传屏障， 艾滋病毒抗药性的出现。世界卫生组织（WHO）于2019年更新了指南 推荐含DTG的方案作为治疗成人、青少年和儿童HIV的首选方案 体重≥20 kg。在非洲，DTG可作为固定剂量复方制剂（FDC）富马酸替诺福韦酯 (TDF)300 mg/拉米夫定（3 TC）300 mg/DTG 50 mg（DDP）和独立50 mg片剂。因此，只有 尽管缺乏来自非洲地区的支持性证据， 临床试验或药代动力学/药效学（PK/PD）研究表明其安全有效。虽然 预期该药在儿童中有效，验证其达到预期的PK和安全性特征 在儿童中很重要。第二个问题是，结核病是非洲艾滋病毒的常见合并症。 对于体重≥20 kg的儿童中的TB/HIV合并感染，也建议使用双倍剂量DTG。迄今为止，DTG 50 尚未在接受含利福平结核治疗的结核病/艾滋病病毒合并感染儿童中进行研究。 多鲁特韦主要通过UDP-葡萄糖醛酸基转移酶1A 1（UGT 1A 1）代谢，贡献较小 （约10%）来自细胞色素P450 3A 4（CYP 3A 4）。UGT 1A 1、ABCG 2和NR 1 I2基因的遗传变异 被确定为DTG PK的显著协变量。DTG不仅对潜在的药物敏感， 由于酶诱导的相互作用，由于遗传和生物学的影响， 协变量，如年龄、营养不良和影响非洲儿童药物吸收的合并症。在 在探索性R21中，我们建议在合格儿童中快速检查DTG的PK和安全性， 随着药物在加纳的推广，我们的主要目标是确定DTG在以下患者中的PK和安全性： 体重≥20 kg的艾滋病毒感染儿童，伴或不伴结核病合并感染。在目标1中，我们将评估PK， 度鲁特韦在未接受过抗逆转录病毒治疗和接受过抗逆转录病毒治疗的儿童和青少年中的安全性 规定的在目标2中，我们将评估利福平治疗期间DTG 50 mg每日两次的PK和安全性。 与儿童停止抗结核治疗后每天50毫克相比， 结核病/艾滋病毒合并感染的青少年。这些目标的成功实现将及时提供证据， 儿童合理使用DTG。拟议的研究不仅意义重大，而且具有创新性， 优先实施下一代艾滋病毒疗法，在关键领域具有更好的安全性和易用性 艾滋病毒相关结核病合并感染治疗的人群和挑战。

项目成果

Pharmacokinetics and pharmacodynamics of adult dolutegravir tablets in treatment-experienced children with HIV weighing at least 20 kg.

成人多替拉韦片剂在体重至少 20 kg 且经历过治疗的 HIV 儿童中的药代动力学和药效学。

• DOI: 10.1097/qad.0000000000003576
• 发表时间: 2023
• 期刊: AIDS (London, England)
• 作者: Martyn-Dickens,Charles;Ojewale,Oluwayemisi;Sly-Moore,Eugenia;Dompreh,Albert;Enimil,Anthony;Amissah,AikinsKofi;Bosomtwe,Dennis;FrimpongAppiah,Augustina;Sarfo,AmaD;Opoku,Theresah;Asiedu,Priscilla;Dong,StephenK;Kusi-Amponsah,Isaa
• 通讯作者: Kusi-Amponsah,Isaa