In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models

多替拉韦缓释制剂在受孕前和妊娠早期动物模型中的安全性和药理学体内评价

基本信息

  • 批准号:
    10246986
  • 负责人:
  • 金额:
    $ 77.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-13 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Title: In vivo evaluation of safety and pharmacology of a sustained release formulation of dolutegravir in pre- conception and early stages of pregnancy Abstract: Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent an important alternative to improve adherence to HIV/AIDS treatment and prevention. Dolutegravir (DTG) is a highly effective ARV drug with low toxicity, improved tolerability, better drug–drug interaction profile, low side-effects, and high genetic barrier to resistance. Due to its excellent properties, dolutegravir became widely used as part of ARV therapies for HIV. Recently, we used dolutegravir for development of an ultra-LA, removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. Although this approach represents a potentially effective strategy for the ultra-LA drug delivery for HIV treatment and prevention, long-time exposure to ARV, especially during pregnancy, raises questions of safety. These concerns are exacerbated by the recent discovery that DTG-based treatment for women in early stages of pregnancy may be associated with several cases of severe neural tube defects (NTDs) in children whose mothers were being treated with DTG. It is thus vital to systematically assess the teratogenic potential of long-term exposures to dolutegravir using relevant in vivo models. Mice are an ideal animal model because they allow for rapid evaluation of drug effects, easy access to embryos, and analysis of drug levels that is not possible in humans. We will use inbred mouse strains with differential sensitivity to NTDs (BALB/cJ, C57BL/6J, and FVB/NJ) as tools for an accurate evaluation of the relative risks of long-term DTG exposure under conditions that are most relevant to the use of DTG in humans: (i) DTG exposure after a single injection of the long-acting DTG formulation designed to improve adherence to drug regimen in humans; (ii) long-term exposure to DTG after daily oral administration as all current ARV regimens are oral; (iii) exposure to DTG in preconception and during pregnancy. We will use acute exposure to DTG at critical stages of embryonic development equivalent to human pregnancy at weeks 3, 4, 5, or 6 to gain insight into the mechanism of potential DTG action during pregnancy. Specifically, this analysis will be able to identify and classify a wide spectrum of potential teratogenic effects observed in human populations in developmental stages of gastrulation and the beginning of neurulation, neural tube closure, the beginning of limb development, and stages following neural tube closure, including palate formation. In addition, we will evaluate the role of the folic acid, one of the most critical factors involved in NTDs. These data will be critical in evaluating and interpreting the human birth defects data that will likely emerge over the next several years. We will also provide a comprehensive analysis of DTG concentration in maternal plasma, placenta, amniotic fluid and embryonic tissues during chronic daily oral DTG administration, after a single dose of a long- acting formulation of DTG and after an acute oral dose of DTG at critical stages of embryonic development. This will allow us to correlate concentration of DTG in embryonic tissues with observed birth defects. Evaluation of teratogenic effect of long-term oral administration of DTG and a long-acting DTG formulation using mouse strains with differential sensitivities to NTD represents a novel and valuable approach to demonstrate the safety profile of DTG in pre-conception and during early stages of pregnancy.
标题:多替拉韦缓释制剂预给药安全性和药理学的体内评价 受孕和怀孕早期阶段 抽象的: 抗逆转录病毒药物 (ARV) 的注射长效 (LA) 制剂是改善病情的重要替代方案 坚持艾滋病毒/艾滋病治疗和预防。多替拉韦 (DTG) 是一种高效的抗逆转录病毒药物,具有低 毒性、改善的耐受性、更好的药物相互作用、低副作用和高遗传屏障 反抗。由于其优异的特性,多替拉韦被广泛用作艾滋病毒抗逆转录病毒疗法的一部分。 最近,我们使用多替拉韦开发了一种超 LA、可拆卸系统,可输送药物最多 9 次。 几个月,可以安全地移除以停止药物输送。尽管这种方法代表了一种潜在的 用于治疗和预防艾滋病毒、长期暴露于抗逆转录病毒药物的超洛杉矶药物输送的有效策略, 尤其是在怀孕期间,会引发安全问题。最近的发现加剧了这些担忧 妊娠早期妇女基于 DTG 的治疗可能与一些病例有关 母亲接受 DTG 治疗的儿童患有严重神经管缺陷 (NTD)。因此至关重要的是 使用相关的体内方法系统地评估长期暴露于多替拉韦的致畸潜力 模型。小鼠是理想的动物模型,因为它们可以快速评估药物效果,易于获得 胚胎和药物水平分析在人类中是不可能的。我们将使用近交系小鼠品系 对 NTD(BALB/cJ、C57BL/6J 和 FVB/NJ)的差异敏感度作为准确评估 NTD 的工具 在与人类使用 DTG 最相关的条件下长期接触 DTG 的相对风险: (i) 单次注射旨在提高依从性的长效 DTG 制剂后的 DTG 暴露 人类的药物治疗方案; (ii) 与目前所有抗逆转录病毒药物一样,每日口服给药后长期暴露于 DTG 治疗方案为口服; (iii) 在孕​​前和怀孕期间接触 DTG。我们将使用急性暴露 胚胎发育关键阶段的 DTG 相当于人类妊娠第 3、4、5 或 6 周时获得的 深入了解 DTG 在妊娠期间的潜在作用机制。具体来说,该分析将能够 识别并分类在人群中观察到的广泛的潜在致畸作用 原肠胚形成的发育阶段和神经形成的开始、神经管闭合、开始 肢体发育以及神经管闭合后的阶段,包括腭形成。此外, 我们将评估叶酸的作用,叶酸是 NTD 中最关键的因素之一。这些数据将 对于评估和解释未来几年可能出现的人类出生缺陷数据至关重要 年。我们还将提供母体血浆、胎盘、 长期每日口服 DTG 给药期间的羊水和胚胎组织,单剂量长期给药后 DTG 的作用制剂以及在胚胎发育关键阶段急性口服 DTG 后的结果。这 将使我们能够将胚胎组织中 DTG 的浓度与观察到的出生缺陷联系起来。评价 长期口服 DTG 和使用小鼠品系的长效 DTG 制剂的致畸作用 对 NTD 具有不同的敏感性,代表了一种新颖且有价值的方法来证明安全性 DTG 在受孕前和妊娠早期阶段的应用。

项目成果

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Martina Kovarova其他文献

Martina Kovarova的其他文献

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{{ truncateString('Martina Kovarova', 18)}}的其他基金

In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models
多替拉韦缓释制剂在受孕前和妊娠早期动物模型中的安全性和药理学体内评价
  • 批准号:
    10469498
  • 财政年份:
    2019
  • 资助金额:
    $ 77.74万
  • 项目类别:
In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models
多替拉韦缓释制剂在受孕前和妊娠早期动物模型中的安全性和药理学体内评价
  • 批准号:
    10674989
  • 财政年份:
    2019
  • 资助金额:
    $ 77.74万
  • 项目类别:
In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models
多替拉韦缓释制剂在受孕前和妊娠早期动物模型中的安全性和药理学体内评价
  • 批准号:
    10018067
  • 财政年份:
    2019
  • 资助金额:
    $ 77.74万
  • 项目类别:

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