Human placental biodisposition of novel antiherpesviral drugs, amenamevir and pritelivir, using ex vivo and in vitro experimental models

使用离体和体外实验模型对新型抗疱疹病毒药物阿美那韦和普替利韦进行人胎盘生物处置

• 批准号: 10682469
• 负责人: Valentina Fokina Bryant
• 金额: $ 41.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682469
• 关键词: ABCB1 gene; Acute; Acyclovir; Affect; Age; Animal Model; Birth; Cells; Cessation of life; Childbirth; Choriocarcinoma; Congenital herpes simplex; DNA Primase; Data; Development; Disease Outbreaks; Embryo; Endothelial Cells; Experimental Models; Exposure to; Fetal safety; Fetus; Goals; Herpes Simplex Infections; Herpes zoster disease; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 2; Immunocompromised Host; In Vitro; Incidence; Individual; Investigation; Japan; Lobule; Mediating; Membrane Transport Proteins; Molecular Weight; Morbidity - disease rate; Mothers; Mus; Neurologic; Newborn Infant; Oryctolagus cuniculus; Patients; Perfusion; Perinatal transmission; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phase III Clinical Trials; Placebos; Placenta; Pregnancy; Pregnant Women; Prodrugs; Recurrence; Reporting; Resistance; Risk; Risk Reduction; Role; Safety; Simplexvirus; Techniques; Therapeutic; Time; Tissues; Toxic effect; Toxicokinetics; Umbilical vein; United States; Virus Shedding; Woman; Work; alternative treatment; clinical development; conventional therapy; developmental toxicity; disability; drug distribution; experience; fetal; genital herpes; hazard; helicase; inhibitor; lipophilicity; men; mortality; neonatal infection; neonate; novel; novel therapeutics; nucleoside analog; placental transfer; pre-clinical; pregnant; prevent; reproductive; response; safety testing; standard care; transmission process; trophoblast; valacyclovir; viral transmission

ABSTRACT Genital herpes simplex virus (HSV) infections in pregnancy pose a risk for perinatal transmission of the virus to neonates, and HSV infections in the newborns are associated with severe morbidity and mortality. A standard treatment of HSV infections with nucleoside analogs such as acyclovir does not eliminate asymptomatic viral shedding and is ineffective against acyclovir-resistant HSV strains. Amenamevir and pritelivir, the helicase-primase inhibitors, represent novel antiherpesviral medications that were developed to circumvent the limitations of the nucleoside analogs. Both novel drugs completed Phase II clinical trials in treatment of genital herpes in men and nonpregnant women and demonstrated superiority over placebo and standard treatments. While amenamevir is currently indicated for the treatment of herpes zoster in Japan, pritelivir received an FDA Breakthrough Therapy designation and has entered a Phase III clinical trial. Pregnant women infected with genital herpes could benefit from amenamevir and pritelivir in suppressive or episodic treatments to prevent the transmission of HSV to neonates. The first step to determine the potential use of the novel drugs in pregnancy is to obtain preclinical data on their placental biodisposition. The focus of the proposed investigation is to determine the biodisposition of amenamevir and pritelivir by human placenta using ex vivo and in vitro experimental models. Meanwhile, assessing fetal safety for amenamevir and pritelivir, as well as their effect on placental function, is imperative in clinical development of these novel drugs for their potential use in pregnancy. While existing data from toxicity studies in animal models suggest a favorable reproductive and developmental safety profile for amenamevir, assessment of potential developmental hazards of pritelivir remains to be conducted. The specific aims are to 1) Determine the extent of bidirectional transfer of amenamevir and pritelivir across term human placenta ex vivo, the distribution of these drugs in the placental tissue and maternal and fetal circuits, and their effect on placental viability and functional parameters; 2) Determine the role of placental efflux membrane transporters in the placental disposition of amenamevir and pritelivir; and 3) Determine potential embryo-fetal developmental toxicity of pritelivir in mice. This work will provide the preclinical data needed to determine potential use of amenamevir and pritelivir in the treatment of newly acquired and reactivated genital herpes in pregnancy as well as in HSV suppressive therapy during pregnancy. Amenamevir and pritelivir could be effective alternative treatments to manage genital herpes in pregnancy to reduce the risk of mother-to-neonate HSV transmission in women with asymptomatic presentation of genital herpes at the time of delivery and for those with inadequate response to standard treatment with nucleoside analogs.

抽象的 妊娠中的生殖器疱疹病毒（HSV）感染构成了围产期传播的风险 新生儿的病毒和新生儿的HSV感染与严重的发病率和死亡率有关。一个 用核苷类似物（如阿昔康维尔）对HSV感染的标准处理不会消除 无症状的病毒脱落，对抗阳性抗性的HSV菌株无效。 Amenamevir和 pritelivir是解旋酶 - 酶抑制剂，代表了新型的抗病毒药物，这些药物已开发为 规避核苷类似物的局限性。两种新型药物均完成了II期临床试验 在男性和未怀孕的女性中治疗生殖器疱疹，并表现出优于安慰剂和 标准治疗。虽然目前指示Amenamevir在日本治疗带状疱疹，但 Pritelivir获得了FDA突破性疗法名称，并已进入了III期临床试验。 感染了生殖器疱疹的孕妇可以从抑制性或 情节处理以防止HSV向新生儿传播。确定潜力的第一步 在怀孕中，新型药物的使用是获取有关其胎盘生物分裂的临床前数据。 拟议的调查的重点是确定amenamevir和pritelivir的生物脱位 使用离体和体外实验模型的人胎盘。同时，评估胎儿安全 Amenamevir和Pritelivir及其对胎盘功能的影响，在临床发展中必须 这些新型药物在怀孕中的潜在使用。而动物毒性研究的现有数据 模型提出了良好的生殖和发育安全性，用于amenamevir，评估 pritelivir的潜在发育危害仍有待实施。具体目的是 1）确定跨期胎盘的双向转移程度 在体内，这些药物在胎盘组织以及母体和胎儿电路中的分布及其 对胎盘生存能力和功能参数的影响； 2）确定胎盘外排膜转运蛋白在Amenamevir胎盘处置中的作用 和pritelivir;和 3）确定pritelivir在小鼠中的潜在胚胎发育毒性。 这项工作将提供确定Amenamevir和Pritelivir潜在用途所需的临床前数据 在怀孕和HSV抑制中的新获得和重新激活的生殖器疱疹的治疗 怀孕期间的治疗。 Amenamevir和Pritelivir可能是管理的有效替代治疗方法 怀孕的生殖器疱疹，以降低患有女性的母亲到神经的HSV传播风险 分娩时生殖器疱疹的无症状表现，对于那些对响应不足的人 核苷类似物的标准处理。