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; 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：在体内对DoluteGravir持续释放公式的安全性和药理学评估 孕育和怀孕的早期阶段 抽象的： 抗逆转录病毒（ARV）的可注射长效（LA）公式代表改进的重要替代方案 遵守艾滋病毒/艾滋病治疗和预防。 Dolutegravir（DTG）是一种高效的ARV药物， 毒性，提高耐受性，更好的药物相互作用曲线，低副作用以及高遗传障碍 反抗。由于其出色的特性，DoluteGravir被广泛用作HIV ARV疗法的一部分。 最近，我们使用Dolutegravir开发了超拉，可移动系统，可提供高达9的药物 几个月，可以安全地删除以停止药物输送。尽管这种方法代表了一种潜在的 超拉药物输送艾滋病毒治疗和预防的有效策略，长期暴露于ARV， 特别是在怀孕期间，提出了安全问题。最近的发现使这些担忧加剧了 在怀孕初期，基于DTG的女性治疗可能与 在母亲接受DTG治疗的儿童中，严重的神经管缺陷（NTD）。因此，对 系统地评估使用相关体内的长期暴露于Dolutegravir的致畸潜力 小鼠是理想的动物模型，因为它们可以快速评估药物效应，轻松访问 胚胎和对人类不可能的药物水平的分析。我们将使用近交小鼠菌株 对NTD（BALB/CJ，C57BL/6J和FVB/NJ）的差异敏感性作为准确评估的工具 在与人类使用DTG最相关的条件下，长期DTG暴露的相对风险： （i）单次注入长效DTG公式后DTG暴露于 人类的毒品疗法； （ii）每天口服后，长期接触DTG作为所有当前ARV 方案是口服的； （iii）在孕前和怀孕期间暴露于DTG。我们将使用急性暴露 胚胎发育的关键阶段的DTG等于第3、4、5或6周的人类怀孕 深入了解怀孕期间潜在DTG作用的机制。具体来说，该分析将能够 识别并分类在人类中观察到的广泛的潜在致致造作用 胃的发展阶段和神经化的开始，神经管封闭，开始 肢体发育和神经管闭合后的阶段，包括味觉形成。此外， 我们将评估叶酸的作用，叶酸是NTD中涉及的最关键因素之一。这些数据将是 评估和解释人类出生缺陷的数据至关重要，这可能会在接下来的几个 年。我们还将对Mater等离子体的DTG浓度进行全面分析，胎盘， 慢性每日口服DTG服用期间，羊水和胚胎组织在单剂 在胚胎发育的关键阶段，DTG的作用公式和DTG急性口服剂量之后。这 将使我们能够与观察到的先天缺陷在胚胎组织中DTG的浓度相关联。评估 长期口服DTG和使用小鼠菌株的长效DTG公式的致畸作用 对NTD的敏感性差异代表了一种新颖而有价值的方法来证明安全性 在概念前和怀孕的早期阶段的DTG。