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

摘要 生殖器单纯疱疹病毒（HSV）感染在怀孕造成的风险， 新生儿中的HSV感染与严重的发病率和死亡率相关。一 用核苷类似物如阿昔洛韦的标准治疗HSV感染并不能消除 无症状的病毒脱落，并且对阿昔洛韦抗性HSV株无效。阿梅那韦和 普利韦是一种解旋酶-引发酶抑制剂，是一种新型抗疱疹病毒药物， 避免了核苷类似物的局限性。这两种新药都在年完成了II期临床试验。 治疗男性和非妊娠女性生殖器疱疹，并证明优于安慰剂， 标准治疗。虽然氨美韦目前在日本被用于治疗带状疱疹， 普瑞利韦获得了FDA突破性治疗的称号，并已进入III期临床试验。 感染生殖器疱疹的孕妇可以从amenamevir和pritelivir中获益， 间歇性治疗，以防止HSV传播给新生儿。第一步确定潜在的 在妊娠期使用新药是为了获得关于其胎盘生物分布的临床前数据。 拟议研究的重点是通过以下方法确定amenamevir和pritelivir的生物处置 使用离体和体外实验模型的人胎盘。同时，评估胎儿安全性， 阿米那韦和普瑞利韦，以及它们对胎盘功能的作用，在临床开发中是必不可少的。 这些新药在怀孕期间的潜在用途。虽然动物毒性研究的现有数据 模型表明，阿米那韦具有良好的生殖和发育安全性， 普雷特利韦的潜在发育危害仍有待研究。具体目标是 1)确定Amenamevir和Pritelivir在足月人胎盘中的双向转移程度 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 对胎盘活力和功能参数的影响; 2)确定胎盘外排膜转运蛋白在阿梅那韦胎盘处置中的作用 和普瑞利韦;和 3)确定pritelivir在小鼠中的潜在胚胎-胎仔发育毒性。 这项工作将提供临床前数据，以确定潜在的使用amenamevir和pritelivir在 治疗妊娠期新获得和复发的生殖器疱疹以及HSV抑制 怀孕期间的治疗。Amenamevir和Pritelivir可能是有效的替代治疗方法， 妊娠期生殖器疱疹，以减少母婴传播的风险， 生殖器疱疹的症状表现在分娩时和那些反应不足， 核苷类似物的标准治疗。

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.