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 妊娠期生殖器单纯疱疹病毒 (HSV) 感染会导致围产期传播该病毒的风险 病毒传染给新生儿，新生儿的 HSV 感染与严重的发病率和死亡率有关。一个 使用核苷类似物（如阿昔洛韦）治疗 HSV 感染并不能消除 无症状病毒脱落，对阿昔洛韦耐药 HSV 株无效。阿美那韦和 普替利韦（pritelivir）是一种解旋酶引物酶抑制剂，代表了新型抗疱疹病毒药物，其开发目的是 规避核苷类似物的局限性。两款新药均已完成II期临床试验 治疗男性和非孕妇的生殖器疱疹，并显示出优于安慰剂和 标准治疗。虽然阿美那韦目前在日本被用于治疗带状疱疹， pritelivir 获得 FDA 突破性疗法认定，并已进入 III 期临床试验。 感染生殖器疱疹的孕妇可以从阿美那韦和普替利韦中获益，以抑制或抑制生殖器疱疹。 间歇性治疗以防止 HSV 传播给新生儿。第一步，确定潜力 在怀孕期间使用新药是为了获得其胎盘生物处置的临床前数据。 拟议研究的重点是通过以下方法确定阿美那韦和普替利韦的生物处置： 使用离体和体外实验模型的人胎盘。同时，评估胎儿安全 阿美那韦和普替利韦及其对胎盘功能的影响对于临床开发至关重要 这些新药在怀孕期间的潜在用途。虽然现有的动物毒性研究数据 模型表明阿美那韦具有良好的生殖和发育安全性，评估 普替利韦的潜在发育危害仍有待研究。具体目标是 1) 确定阿美那韦和普替利韦跨足月人胎盘的双向转移程度 离体，这些药物在胎盘组织和母体和胎儿回路中的分布及其作用 对胎盘活力和功能参数的影响； 2) 确定胎盘流出膜转运蛋白在阿美那韦胎盘处置中的作用 和普替利韦；和 3) 确定普替利韦对小鼠的潜在胚胎-胎儿发育毒性。 这项工作将提供确定阿美那韦和普替利韦在治疗中的潜在用途所需的临床前数据。 妊娠期新发和复发的生殖器疱疹的治疗以及 HSV 抑制 怀孕期间的治疗。阿美那韦和普替利韦可能是有效的替代疗法 妊娠期生殖器疱疹可降低患有生殖器疱疹的妇女将 HSV 传播给新生儿的风险 分娩时无症状的生殖器疱疹以及对治疗反应不足的人 核苷类似物的标准治疗。