PACTG P1026S (VERSION 20), PHARMACOKINETIC PROPERTIES OF ANTIRETROVIRAL DRUG

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 假设 研究抗逆转录病毒药物在孕妇体内药代动力学的临床试验有限。 为孕妇制定适当的给药方案对母亲和胎儿的健康至关重要。 过量给药可能导致母体不良事件和胎儿毒性风险增加。 剂量不足可能导致病毒学控制不足，增加产生耐药性突变的风险，以及提高围产期艾滋病毒传播率。 怀孕期间代谢增加和免疫反应抑制都可能使母亲面临病毒突破和疾病进展的风险。 独立于药理学因素，孕妇可能处于艾滋病毒疾病进展的特殊风险中。 妊娠在抗原性不同的组织之间产生暂时的生理和免疫稳态。 为了适应胎儿，母体免疫系统至少部分受到抑制，糖皮质激素升高（涉及诱导肝脏代谢）作为这种反应的一个组成部分。 具体目标 主要目的：描述目前用于妊娠HIV感染女性临床护理的选定抗逆转录病毒药物在妊娠期间的PK参数，并确定这些抗逆转录病毒药物的治疗性给药方案是否在妊娠期间产生足够的药物暴露，与a）非妊娠成人的历史数据;和B）研究队列中相同女性在产后期间相比。 次要目的：比较分娩时脐带血和母体血浆中抗逆转录病毒药物的浓度。 通过测定尿液中6 B-羟基皮质醇与皮质醇的比值，间接评估细胞色素P450 3A 4的诱导作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HYPOTHESIS Clinical trials to study the pharmacokinetics of antiretroviral drugs in pregnant women are limited. The development of appropriate dosing regimens for the pregnant woman is critical to the health of both mother and fetus. Overdosing may lead to maternal adverse events and increased risk of fetal toxicity. Underdosing may lead to inadequate virologic control, increased risk of developing drug resistance mutations and a higher rate of perinatal HIV transmission. Both increased metabolism and suppressed immunologic response during pregnancy can leave the mother at risk for viral breakthrough and progression of disease. Independent of pharmacologic factors, pregnant women may be at particular risk for progression of their HIV disease. Pregnancy produces a temporary physiologic and immunologic homeostatis between tissues that are antigenically different. In order to accommodate the fetus, the maternal immune system is at least partially suppressed with an elevation of glucocorticoids (implicated in inducing hepatic metabolism) as one component of this response. SPECIFIC AIMS Primary Objective: To describe the PK parameters during pregnacy of selected antiretroviral drugs currently used in the clinical care of pregnant HIV-infected women, and to determine if therapeutic dosing regimens of these antiretroviral drugs produce adequate drug exposure during pregnancy compared to a) historical data from non-pregnant adults; and b) the same women in the study cohorts during the postpartum period. Secondary Obectives: To compare antiretroviral drug concentrations is plasma from cord blood with those in maternal plasma at the time of delivery. To indirectly assess the induction of cytochrome P450 3A4 by determining the ratio in urine of 6B-hydroxycortisol to cortisol.