Plausible Causative Mechanism for Dolutegravir Developmental Toxicity

多替拉韦发育毒性的可能致病机制

• 批准号: 10240603
• 负责人: Robert M Cabrera
• 金额: $ 67.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240603
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse event; Affect; Animal Model; Animals; Apoptosis; Binding; Biochemical; Biological Assay; Birth; Blood; Botswana; Buffers; Calcium; Carbon; Cations; Cell Line; Cell model; Cells; Child; Clinical; Cohort Studies; Competitive Binding; Conceptions; Congenital Abnormality; Data; Development; Developmental Process; Developmental Toxicant; Diet; Dosage Forms; Dose; Embryo; Embryonic Development; Erythrocytes; Exposure to; FOLR1 gene; Fetal Tissues; Folic Acid; Folic Acid Antagonists; HIV; HIV Seropositivity; Healthcare; Human; Immunofluorescence Immunologic; Impairment; In Vitro; Incidence; Infant; Integrase Inhibitors; Intervention; Iron; Label; Link; Manufacturer Name; Measures; Membrane; Modeling; Molecular and Cellular Biology; Mothers; Mus; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neurologic; Outcome; Pathology; Patients; Pattern; Pharmaceutical Preparations; Physiological; Placenta; Plasma; Pregnancy; Pregnant Women; Prevalence; Regimen; Reporting; Reproduction; Research; Research Proposals; Risk; Risk Factors; Role; Serum; Specificity; System; Teratogens; Testing; Time; Tissues; Toxic effect; Woman; Work; Zebrafish; animal tissue; antiretroviral therapy; base; chelation; child bearing; clinically relevant; developmental toxicity; embryo tissue; experience; folate-binding protein; mouse model; novel; offspring; placental mammal; prenatal exposure; programs; rapid testing; response; surveillance study; therapeutically effective; trophoblast; uptake

Abstract The human immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG) has emerged as a leading core agent. The DTG/Tivicay manufacturer reports (09/2018) that animal reproduction studies showed no evidence of adverse developmental outcomes, but an ongoing observational human cohort study in Botswana initially reported a 9-fold increase for neural tube defect (NTD) risk in offspring from mothers receiving DTG. With increased exposed births but no additional NTDs, a 6-fold increase for NTD risk in infants with early gestational exposure to DTG still remains. Recent concerns about teratogenicity have led to caution for DTG-based regimen use in women of child-bearing potential. We hypothesized that if DTG is teratogenic, then embryonic exposure to DTG will result in changes to one or more essential developmental processes, affecting functional mechanisms that have direct roles in neurulation and NTDs. We report a mechanism of action (MOA) for DTG teratogenicity and demonstrate specificity of this MOA in an animal model by rescue of DTG-induced developmental toxicity. Competitive binding data indicates DTG is a partial antagonist of folate receptors at clinically relevant concentrations. Data from the zebrafish model show developmental toxicity due to early embryonic exposure to DTG. Specificity of DTG developmental toxicity is demonstrated via rescue of DTG-induced developmental toxicity by supplemental folate. Folates and folate receptor are established modifiers of risk for NTDs, and these data indicate DTG is an antagonist of folate receptor and developmental toxicant at clinically relevant concentrations.

摘要