A Phase 1 Pharmacokinetic Trial of Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination in Pregnant Women with Chronic Hepatitis C Virus Infection

Ledipasvir/Sofosbuvir (LDV/SOF) 固定剂量组合在慢性丙型肝炎病毒感染孕妇中的 1 期药代动力学试验

• 批准号: 9185652
• 负责人: Catherine Chappell
• 金额: $ 28.97万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185652
• 关键词: Adherence; Aftercare; Age; Age-Months; Americas; Animal Model; Antiviral Agents; Antiviral Therapy; Area; Birth; Blood; Caring; Categories; Child; Chronic Hepatitis C; Cirrhosis; Clinic Visits; Communicable Diseases; Communities; Data; Detection; Development; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Emotional; Ensure; Evaluation; Event; Excretory function; Exposure to; Fetus; Future; Generations; Genotype; Gestational Age; Growth; Guidelines; HIV; Health; Healthcare; Hepatitis C; Hepatitis C Transmission; Hepatitis C virus; Incidence; Infant; Institution; Interferons; Intervention; Liver diseases; Maternal Health; Measures; Metabolism; Monitor; Morbidity - disease rate; Mothers; Neonatal; Oral; Oral Administration; Patients; Perinatal; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Examination; Physiological; Plasma; Polymerase; Postpartum Period; Pregnancy; Pregnant Women; Prenatal care; Prevalence; Prevention; Primary carcinoma of the liver cells; Reporting; Research Infrastructure; Ribavirin; Risk; Safety; Sampling; Second Pregnancy Trimester; Societies; Third Pregnancy Trimester; Time; Toddler; Treatment Efficacy; Treatment Protocols; United States; Viral; Visit; Woman; absorption; adverse pregnancy outcome; arm; base; design; disorder prevention; effective intervention; experience; health care service utilization; improved; inhibitor/antagonist; liver transplantation; neonatal outcome; open label; phase 1 study; pill; pre-clinical; preclinical evaluation; prevent; reproductive; response; social; treatment duration; treatment response; unborn child; viral RNA

PROJECT SUMMARY There are 3.2 million persons in the United States chronically infected with hepatitis C virus (HCV) with a 1- 2.4% prevalence during pregnancy. The recent October 2014 approval of the fixed dose combination, containing the NS5B polymerase inhibitor sofosbuvir (SOF) 90 mg and the NS5A inhibitor ledipasvir (LDV) 400mg, marked a new era of IFN and ribavirin free, directly acting antiviral treatment for HCV. A 12 week treatment course of LDV/SOF resulted in a 99% cure rate when given as a once-a-day oral pill. Based on the animal model data submitted to the FDA, this drug combination was given a pregnancy category B designation, even though there is currently no experience with LDV/SOF in pregnant women. Pregnancy is a time when women are uniquely motivated to engage in activities which are geared toward improvement of their own health and ensuring the health of their unborn child. As such, pregnant women have frequent prenatal care visits; and health care interventions, such as antiviral therapy and monitoring, can be easily integrated into the existing healthcare infrastructure of prenatal care. The benefits of HCV treatment are numerous, including prevention of severe liver disease, hepatocellular carcinoma, and liver transplantation, as well as improvements physical, emotional and social health. The most recent guidelines by the Infectious Disease Society of America recommend that all HCV-infected persons receive treatment. The antenatal period represents an ideal window of opportunity for treatment of HCV in pregnancy due to increased antenatal health care utilization and prevention of perinatal transmission of HCV to the infant. Safe administration of drugs in pregnancy may require dose adjustment due to the pregnancy-induced physiologic alternations. Therefore, careful pharmacokinetic (PK) evaluation is a critical first step to ensure safe administration of drugs to both the mother and the developing fetus. In this R21 application, we propose a single-arm, single-center, open label Phase 1 evaluation of the PK and safety of treating HCV with a 12 week course of LDV/SOF in 15 HCV-infected pregnant women. Therapy will be initiated at approximately 24 weeks of gestation. In this study we will determine: 1) if the PK of the LDV and SOF are similar in pregnancy as compared to those in nonpregnant women, 2) if the viral response to LDV/SOF treatment in pregnancy is similar to that observed in nonpregnant women, and 3) if there are any initial maternal or neonatal safety concerns detected with antenatal LDV/SOF administration compared with HCV-infected historical controls delivered at our institution. From the findings of this study, future studies will seek to optimize the dose, gestational age timing and treatment duration of LDV/SOF during pregnancy. Antenatal HCV treatment will improve maternal health, prevent further HCV transmission in the community and perinatal HCV transmission to the child, and thus enhance the long-term health of two generations.

项目摘要 在美国有320万人慢性感染丙型肝炎病毒（HCV），1- 怀孕期间的患病率为2.4%。最近2014年10月批准的固定剂量组合， 含有NS 5 B聚合酶抑制剂索非布韦（SOF）90 mg和NS 5A抑制剂ledipasvir（LDV） 400毫克，标志着一个新时代的干扰素和利巴韦林免费，直接作用的抗病毒治疗丙型肝炎病毒。12周 LDV/SOF的治疗过程导致99%的治愈率，当作为一天一次的口服药丸给药时。基于 根据提交给FDA的动物模型数据，该药物组合被给予妊娠类别B 尽管目前尚无LDV/SOF在孕妇中的经验，但仍有一些人被指定为LDV/SOF。 怀孕是一个时间，当妇女是独特的动机，从事活动，这是面向 改善她们自身的健康并确保其未出生婴儿的健康。因此，孕妇有 频繁的产前检查;和卫生保健干预，如抗病毒治疗和监测，可以 很容易整合到现有的产前保健基础设施中。HCV治疗的好处是 许多，包括预防严重肝病，肝细胞癌和肝移植， 以及改善身体、情绪和社会健康。传染病委员会的最新指南 美国疾病协会建议所有HCV感染者接受治疗。产前时期 由于产前健康的提高，代表了治疗妊娠期HCV的理想机会窗口 护理利用和预防HCV向婴儿的围产期传播。 妊娠期安全给药可能需要调整剂量，因为妊娠诱导 生理变化因此，仔细的药代动力学（PK）评价是确保 对母亲和发育中的胎儿安全给药。在这个R21应用中，我们提出了一个 单组、单中心、开放标签、1期研究，评价12周治疗HCV的PK和安全性 15例HCV感染孕妇的LDV/SOF病程。治疗将在大约24周时开始 妊娠期。在本研究中，我们将确定：1）LDV和SOF的PK在妊娠期是否相似， 与非妊娠妇女相比，2）如果妊娠期对LDV/SOF治疗的病毒应答 类似于在非妊娠妇女中观察到的，以及3）是否存在任何初始的母体或新生儿安全性 与HCV感染的历史对照相比，产前LDV/SOF给药检测到的问题 在我们的机构交付。从这项研究的结果来看，未来的研究将寻求优化剂量， 妊娠期间LDV/SOF的胎龄时间和治疗持续时间。丙肝治疗将 改善孕产妇健康，预防社区和围产期HCV传播的进一步传播 为孩子提供健康的生活方式，从而促进两代人的长期健康。