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

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