Plausible Causative Mechanism for Dolutegravir Developmental Toxicity

摘要 人类免疫缺陷病毒（HIV）整合酶抑制剂越来越多地用于 抗逆转录病毒疗法（ART）和度鲁特韦（DTG）已成为主要的核心药物。的 DTG/Tivicay生产商报告（2018年9月），动物生殖研究显示，没有证据表明 不利的发展结果，但正在博茨瓦纳进行的一项观察性人类队列研究 最初报告说，母亲接受神经管缺陷（NTD）的风险增加了9倍， DTG。随着出生暴露增加，但没有额外的NTD，婴儿NTD风险增加6倍 妊娠早期暴露于DTG的风险仍然存在。最近对致畸性的关注导致了 在有生育能力的女性中使用基于DTG的方案时应谨慎。我们假设如果DTG 是致畸的，那么胚胎暴露于DTG将导致一个或多个基本的变化， 发育过程，影响在神经形成中有直接作用的功能机制， NTD。我们报告了DTG致畸性的作用机制（MOA），并证明了DTG的特异性。 这种MOA在动物模型中通过拯救DTG诱导的发育毒性。竞争性结合 数据表明DTG在临床相关浓度下是叶酸受体的部分拮抗剂。数据 来自斑马鱼模型的小鼠显示由于早期胚胎暴露于DTG而导致的发育毒性。 DTG发育毒性的特异性通过DTG诱导的发育毒性的拯救来证明。 补充叶酸的毒性叶酸和叶酸受体是确定的NTD风险调节剂， 提示DTG在临床上是叶酸受体拮抗剂和发育毒物 相关浓度。

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.