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
• 负责人: Martina Kovarova
• 金额: $ 77.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018067
• 关键词: AIDS/HIV problem; Acute; Address; Adherence; Adult; Affect; Amniotic Fluid; Animal Model; Anti-Retroviral Agents; Brain; Child; Chronic; Clinical Research; Congenital Abnormality; Data; Defect; Development; Developmental Disabilities; Dose; Drug Delivery Systems; Drug Evaluation; Drug Interactions; Drug Kinetics; Embryo; Embryonic Development; Evaluation; Exposure to; Female; First Pregnancy Trimester; Folic Acid; Formulation; Genetic; Goals; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Human; Inbred Strains Mice; Injectable; Injections; Integrase; Investigation; Knowledge; Limb Development; Long-Term Effects; Mediating; Modeling; Mothers; Mouse Strains; Mus; Neural Tube Closure; Neural Tube Defects; Neural tube; Oral; Oral Administration; Palate; Penetrance; Penetration; Pharmaceutical Preparations; Pharmacology; Phenotype; Placebos; Placenta; Plasma; Population; Predisposition; Pregnancy; Prevention; Prevention strategy; Property; Publishing; Recommendation; Regimen; Relative Risks; Reporting; Resistance; Role; Safety; Spinal Cord; Sustainable Development; System; Tablets; Teratogenic effects; Teratogens; Testing; Time; Toxic effect; Vertebral column; Viral Load result; Woman; analog; antiretroviral therapy; base; design; developmental toxicology; dosage; early pregnancy; embryo tissue; experimental study; folic acid supplementation; gastrulation; improved; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; insight; medication safety; mouse model; novel; offspring; peripheral blood; pregnant; prevent; reproductive tract; research study; safety testing; side effect; tool; treatment comparison

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：多洛替格雷缓释制剂在体内的安全性和药理学评价 受孕与妊娠早期 摘要： 抗逆转录病毒药物(ARV)的注射长效(LA)制剂是改善 坚持艾滋病毒/艾滋病治疗和预防。多洛替格雷(DTG)是一种高效、低毒的抗逆转录病毒药物。 毒性，更好的耐受性，更好的药物相互作用模式，低副作用，以及高遗传屏障 抵抗。由于其优异的性能，多洛替格列韦被广泛用于艾滋病毒的抗逆转录病毒疗法。 最近，我们使用多洛替格列韦开发了一种超LA、可拆卸的系统，可以将药物输送到9 几个月后，可以安全地取出以阻止药物输送。尽管这种方法可能是一种 用于艾滋病毒治疗和预防的超LA药物输送的有效策略，长期暴露于ARV， 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 妊娠早期基于DTG的治疗可能与几个病例有关 母亲接受DTG治疗的儿童患有严重的神经管缺陷(NTDS)。因此，至关重要的是 使用相关的体内试验系统地评估长期接触多洛替格韦的致畸潜力 模特们。小鼠是一个理想的动物模型，因为它们允许快速评估药物效果，很容易获得 胚胎，以及对药物水平的分析，这在人类是不可能的。我们将使用近交系小鼠品系 对NTDS(BALB/CJ、C57BL/6J和FVB/NJ)的差异敏感性作为准确评估 在与人体使用DTG最相关的条件下长期接触DTG的相对风险： (I)单次注射长效DTG制剂后的DTG暴露，旨在改善对 人类的药物方案；(2)在每日口服后长期接触DTG，作为目前所有的ARV 治疗方案是口服的；(3)在怀孕前和怀孕期间暴露于DTG。我们将使用急性暴露于 DTG处于胚胎发育的关键阶段，相当于人类在怀孕3、4、5或6周时获得 深入了解妊娠期DTG的潜在作用机制。具体地说，这种分析将能够 识别和分类在人群中观察到的广泛的潜在致畸效应 原肠形成的发育阶段和神经形成的开始，神经管闭合，开始 肢体发育的阶段，以及神经管闭合后的阶段，包括腭部形成。此外, 我们将评估叶酸的作用，叶酸是NTDS中最关键的因素之一。这些数据将是 在评估和解释可能在未来几年出现的人类出生缺陷数据方面至关重要 好几年了。我们还将全面分析孕妇血浆、胎盘、 羊水和胚胎组织在慢性每日口服DTG的过程中，在单次剂量后，长期- 在胚胎发育的关键阶段急性口服DTG后，服用DTG的有效制剂。这 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。评估 长期口服丹参及其长效制剂对小鼠致畸作用的研究 对NTD的区分敏感性代表了一种新的、有价值的方法来证明安全性 DTG在受孕前和妊娠早期的变化。