PHARMACOLOGIC EVALUATION OF HIV-INFECTED PREGNANT WOMEN ON HAART

HIV 感染孕妇接受 HAART 的药理学评价

• 批准号: 7605137
• 负责人: JENNIFER JUSTICE KISER
• 金额: $ 5.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605137
• 关键词: AIDS clinical trial group; Address; Adherence; Adverse effects; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Area; Binding; Blood; Caring; Colorado; Computer Retrieval of Information on Scientific Projects Database; Counseling; Data; Dose; Drug Formulations; Drug Kinetics; Drug Monitoring; Effectiveness; End Point; Enrollment; Equilibrium; Evaluation; Female; Funding; Grant; Guidelines; Hour; Immunologic Deficiency Syndromes; Individual; Institution; Laboratories; Lamivudine/Zidovudine; Lopinavir/Ritonavir; Measures; Names; Nelfinavir; Nucleosides; Numbers; Parents; Participant; Patient currently pregnant; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Population; Postpartum Period; Pregnancy; Pregnant Women; Probability; Protease Inhibitor; Protein Binding; Publishing; Randomized; Recommendation; Research; Research Personnel; Resources; Reverse Transcriptase Inhibitors; Risk; Sampling; Saquinavir; Schedule; Source; Standards of Weights and Measures; Stavudine; System; Tablets; Therapeutic; Third Pregnancy Trimester; Time; United States; United States Dept. of Health and Human Services; United States National Institutes of Health; Universities; Upper arm; Viral Load result; Visit; Week; Woman; Zidovudine; absorption; abstracting; antiretroviral therapy; base; cohort; dietary requirement; dosage; improved; male; programs; response; sex; tripolyphosphate; viracept

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Department of Health and Human Services recommends that therapies of known benefit not be withheld from pregnant women unless the risks clearly outweigh the benefits. Since 1997, antiretroviral therapy with a combination of approved anti-HIV agents has been the standard of care in the United States for those who meet treatment criteria, including pregnant women. Currently, treatment with the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and lamivudine and a protease inhibitor (PI) is most frequently prescribed to pregnant women cared for through the Children's Hospital Immunodeficiency Program (CHIP) at The Children's Hospital. The Department of Health and Human Services (DHHS) Treatment Guidelines also recommend plasma therapeutic drug monitoring of PIs during pregnancy. Accordingly, CHIP performs plasma peak and trough levels of the PIs in pregnant women, and dose adjusts if trough levels are lower than expected. Several studies have demonstrated improved virologic suppression with therapeutic drug monitoring in non-pregnant individuals. In particular, AIDS Clinical Trials Group Study (ACTG) 359, a study examining sex-based differences in saquinavir (a PI) pharmacology and virologic response, demonstrated that males had a lower probability of having viral loads < 500 copies/mL at study endpoint than did females. This difference was attributed to the fact that females had higher plasma concentrations of saquinavir than did males. There have not yet been any longitudinal therapeutic drug monitoring studies conducted during pregnancy. [1] There is little information on the effect of pregnancy on antiretroviral drug pharmacokinetics. It is important to not only study the plasma pharmacokinetics of the antiretroviral drugs, but also to quantify the active moieties of these drugs since essentially all physiologic systems are altered during pregnancy. The active moieties of the NRTIs are the intracellular triphosphorylated parent drug. A sizable amount of plasma NRTI data are available, yet no data exist on the intracellular pharmacokinetics of the active triphosphorylated analyte of these agents during pregnancy. While the PIs do not require an intracellular transformation to exert their effect, they are highly protein bound agents. Only unbound drug is available to produce an effect. There are some studies that have intensively quantified plasma levels of the PIs during pregnancy, yet none have published information on unbound concentrations. This proposal aims to characterize the plasma, intracellular, and unbound pharmacokinetic disposition of antiretroviral agents during pregnancy and the pharmacokinetic efficacy of PI dosage adjustment. This study will enroll pregnant women who are cared for by CHIP at The Children's Hospital. Thirty pregnant women (less than 22 weeks gestation) will be entered into one of two groups. Abstract Table: Treatment Cohorts Group Nucleoside reverse transcriptase inhibitor (NRTI)* Protease Inhibitor (brand name) and Formulation I zidovudine + lamivudine nelfinavir (Viracept¿) 625 mg tablet II zidovudine + lamivudine lopinavir/ritonavir (Kaletra¿) 200/50 mg tablet *stavudine may be substituted for zidovudine in certain circumstances (see Section I) Group 1 will include women on zidovudine and lamivudine plus nelfinavir. Group 2 will include women on zidovudine and lamivudine plus lopinavir/ritonavir. Women who present to CHIP already on antiretroviral therapy which includes zidovudine and lamivudine plus nelfinavir or lopinavir/ritonavir may enroll without randomization. Otherwise, women who present to CHIP not already on therapy will be randomized to either nelfinavir or lopinavir/ritonavir and will be prescribed the NRTI combination zidovudine and lamivudine. In order to assure balance between the two groups, the randomization will control for the number of subjects on each arm; whereby the probability of being randomized to either arm is a function of the distribution of subjects already on study. Intensive plasma NRTI and PI sampling (9 determinations at 1-2 hour intervals) will occur once during the 2nd and 3rd trimesters. Also during these intensive pharmacokinetic visits, intracellular triphosphate concentrations (ICTP) of zidovudine and lamivudine will be determined at pre-dose and 4 hours post-observed dose, and unbound PI concentrations will be determined at pre-dose, 2-, 4-, and 8-hr post-observed dose. Pharmacologic evaluations will be conducted in real time by the University of Colorado Antiviral Pharmacology Laboratory (Director: CV Fletcher). These intensive pharmacokinetic profiles will allow for non-compartmental analysis of pharmacokinetic parameters, including the area-under-the-concentration-time curve (AUC) of the PIs. If the AUC value is below the historic population 25th percentile and/or the minimum concentration (Cmin) is below the 50th percentile, a dosage adjustment of the PI component will be recommended within two weeks of the intensive pharmacokinetic visit. Approximately two weeks following the dosage recommendation of the PI (whether adjusted, or not), another short study visit will take place to assess the trough bound and unbound concentrations of the PI, and blood will be collected for ICTP NRTI quantification. These short study visits will be repeated again following the third trimester intensive pharmacokinetic visit. Lastly, postpartum plasma trough levels of the antiretroviral drugs will be collected 2 weeks postpartum for those women who remain on antiretroviral therapy. Blood will once again be collected for ICTP quantification and unbound PI concentrations postpartum. An important component to pharmacokinetic analysis includes adherence counseling. Each study participant's adherence will be addressed by investigators during scheduled study visits, including a discussion of the necessary dietary requirements to obtain adequate absorption and reduced adverse effects attributed to each medication the patient is receiving. The importance of this study resides in the fact that it will generate plasma bound and unbound pharmacokinetic data for the 625 mg nelfinavir tablet formulation and for the 200/50 mg lopinavir/ritonavir tablet formulation. In addition, for the first time, ICTP NRTI levels will be measured during pregnancy. It will also provide information on the effectiveness of pharmacokinetic-guided dose adjustments of nelfinavir and lopinavir/ritonavir during pregnancy, and will allow a longitudinal description of individual pharmacokinetic parameters, beginning in the 2nd trimester and through the postpartum period.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 卫生与公共服务部建议，除非有可能胜过福利，否则孕妇的疗法不会被扣留。自1997年以来，与符合治疗标准（包括孕妇在内的治疗标准）的抗逆转录病毒疗法，与批准的抗HIV药物结合在一起一直是美国的护理标准。目前，用核方逆转录酶抑制剂（NRTIS）Zidovudine和Lamivudine治疗以及蛋白质抑制剂（PI）的治疗最常被儿童医院儿童医院免疫缺陷计划（CHIP）所照顾的孕妇开处方。卫生与公共服务部（DHHS）治疗指南还建议怀孕期间PIS的血浆治疗药物监测。根据以下内容，CHIP在孕妇中执行血浆峰和PI的故障水平，并且如果故障水平低于预期，则剂量会调整剂量。几项研究表明，通过非妊娠个体的治疗药物监测改善了病毒学抑制作用。特别是，AIDS临床试验小组研究（ACTG）359是一项研究，该研究研究了基于性别的saquinavir（PI）药理学和病毒学反应的差异，表明男性在研究端点的病毒载荷<500份/mL的可能性较低。这种差异归因于以下事实：女性的血浆浓度比男性高。怀孕期间尚未进行任何纵向治疗药物监测研究。 [1] 关于妊娠对抗逆转录病毒药物药物的影响的信息很少。重要的是，不仅研究抗逆转录病毒药物的血浆药代动力学，而且要量化这些药物的活性部分，因为在怀孕期间所有生理系统基本上都在改变。 NRTI的活性部分是细胞内三磷酸化的母体。提供大量的血浆NRTI数据，但在怀孕期间这些药物的活性三磷酸化分析物的细胞内药代动力学没有数据。虽然PI不需要细胞内转化即可执行其效果，但它们是高度蛋白质结合的药物。只有未结合的药物可以产生效果。有些研究在怀孕期间对PI的血浆水平进行了大量量化，但没有一项发表有关未结合浓度的信息。该提案旨在表征抗逆转录病毒药物在怀孕期间的血浆，细胞内和未结合的药代动力学分配以及PI剂量调整的药代动力学效率。 这项研究将招募在儿童医院受到CHIP照顾的孕妇。三十名孕妇（妊娠不到22周）将分为两组之一。 摘要表：治疗队列 组核苷逆转录酶抑制剂（NRTI）*蛋白酶抑制剂（品牌名称）和配方 i Zidovudine + Lamivudine Nelfinavir（Viracept¿）625 mg平板电脑 II Zidovudine + Lamivudine Lopinavir/Ritonavir（Kaletra¿）200/50毫克平板电脑 *在某些情况下，可以用Stavudine代替Zidovudine（请参阅第I节） 第1组将包括Zidovudine和Lamivudine Plus Nelfinavir的妇女。第2组将包括Zidovudine和Lamivudine Plus Lopinavir/Ritonavir的妇女。已经接受抗逆转录病毒疗法的筹码的妇女，其中包括齐多夫丁和拉米夫丁加尼尔菲那韦或lopinavir/ritonavir，可能不会随机招募。否则，尚未接受治疗的妇女将被随机分为Nelfinavir或Lopinavir/Ritonavir，并将开处方NRTI组合Zidovudine和Lamivudine。为了确保两组之间的平衡，随机化将控制每个手臂上的受试者数量；因此，被随机分配到任何一个ARM的概率是已经在研究中的受试者分布的函数。 在第二和第3个三物质期间，将一次进行一次密集的血浆NRTI和PI采样（9个时间间隔测定）一次。同样，在这些密集的药代动力学访问期间，齐多夫丁和拉米夫丁的细胞内三磷酸浓度（ICTP）将在剂量前和斑点后剂量后4小时确定，并在预剂量，2-，4--，4--和8 hr术后剂量剂量下确定未结合的PI浓度。药理学评估将由科罗拉多大学抗病毒药理学实验室实时进行（总监：CV Fletcher）。这些密集的药代动力学特征将允许对药代动力学参数的非室内分析，包括PIS的浓缩时间曲线（AUC）。如果AUC值低于历史人口25％和/或最低浓度（CMIN）低于50％的AUC人口，则建议在强化药物访问后的两周内对PI组件进行剂量调整。 PI剂量推荐后约两个星期（无论是否调整），将进行另一项简短的研究访问，以评估PI的困扰和未结合的浓度，并将收集血液以进行ICTP NRTI量化。这些简短的研究访问将在第三个孕期强化药代动力学访问后再次重复。最后，抗逆转录病毒药物的产后血浆水平将在产后2周收集那些继续接受抗逆转录病毒疗法的妇女。血液将再次收集以进行ICTP定量和产后未结合的PI浓度。 药代动力学分析的重要组成部分包括依从性咨询。每个研究参与者的依从性将在预定的研究访问期间得到解决，包括讨论必要的饮食要求，以获得足够的缓解，并减少归因于患者接受的每种药物的不良反应。 这项研究的重要性在于，它将为625 mg Nelfinavir片剂以及200/50 mg lopinavir/Ritonavir片剂配方生成血浆结合和未结合的药代动力学数据。此外，在怀孕期间将首次测量ICTP NRTI水平。它还将提供有关妊娠期间Nelfinavir和Lopinavir/Ritonavir的药代动力学指导剂量调整的有效性的信息，并允许对单个药代动力学参数的纵向描述，始于第二三药，并在后产后。