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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 卫生与公共服务部建议，除非风险明显大于益处，否则不要拒绝对孕妇进行已知益处的治疗。 自 1997 年以来，联合经批准的抗 HIV 药物的抗逆转录病毒治疗一直是美国符合治疗标准的患者（包括孕妇）的标准治疗方法。 目前，儿童医院儿童医院免疫缺陷项目 (CHIP) 护理的孕妇最常接受核苷逆转录酶抑制剂 (NRTI) 齐多夫定和拉米夫定以及蛋白酶抑制剂 (PI) 的治疗。 卫生与公众服务部 (DHHS) 治疗指南还建议在怀孕期间对 PI 进行血浆治疗药物监测。 因此，CHIP 会检测孕妇 PI 的血浆峰值和谷值水平，如果谷值水平低于预期，则会调整剂量。 几项研究表明，通过对非怀孕个体进行治疗药物监测可以改善病毒学抑制。 特别是，艾滋病临床试验组研究 (ACTG) 359 是一项检查沙奎那韦 (a PI) 药理学和病毒学反应中基于性别的差异的研究，该研究表明，在研究终点时，男性病毒载量 < 500 拷贝/mL 的可能性低于女性。这种差异归因于女性的沙奎那韦血浆浓度高于男性。 尚未在怀孕期间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代动力学影响的信息很少。 不仅研究抗逆转录病毒药物的血浆药代动力学，而且量化这些药物的活性部分也很重要，因为基本上所有生理系统在怀孕期间都会发生改变。 NRTI 的活性部分是细胞内三磷酸化的母体药物。 可获得大量血浆 NRTI 数据，但尚无关于妊娠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的数据。 虽然 PI 不需要细胞内转化来发挥其作用，但它们是高度蛋白质结合剂。只有未结合的药物才能产生效果。 有一些研究对怀孕期间 PI 的血浆水平进行了深入量化，但尚未发表有关未结合浓度的信息。 该提案旨在表征妊娠期间抗逆转录病毒药物的血浆、细胞内和未结合的药代动力学分布以及 PI 剂量调整的药代动力学功效。 这项研究将招募在儿童医院接受 CHIP 护理的孕妇。 30 名孕妇（妊娠少于 22 周）将被分入两组中的一组。 摘要表：治疗队列 组别 核苷逆转录酶抑制剂 (NRTI)* 蛋白酶抑制剂（商品名）和制剂 I 齐多夫定 + 拉米夫定奈非那韦 (Viracept¿) 625 毫克片剂 II 齐多夫定 + 拉米夫定 洛匹那韦/利托那韦 (Kaletra¿) 200/50 mg 片剂 *在某些情况下司他夫定可以替代齐多夫定（参见第一部分） 第一组包括服用齐多夫定和拉米夫定加奈非那韦的女性。 第 2 组包括服用齐多夫定和拉米夫定加洛匹那韦/利托那韦的女性。 已经接受 CHIP 抗逆转录病毒治疗（包括齐多夫定和拉米夫定加奈非那韦或洛匹那韦/利托那韦）的女性可以不随机入组。 否则，尚未接受治疗的向 CHIP 报告的女性将被随机分配到奈非那韦或洛匹那韦/利托那韦，并开具 NRTI 组合齐多夫定和拉米夫定。 为了确保两组之间的平衡，随机化将控制每组的受试者数量；其中，被随机分配到任一组的概率是已在研究的受试者分布的函数。 密集血浆 NRTI 和 PI 采样（每隔 1-2 小时进行 9 次测定）将在第二个和第三个三个月期间进行一次。 此外，在这些密集的药代动力学访视期间，将在给药前和观察剂量后 4 小时测定齐多夫定和拉米夫定的细胞内三磷酸盐浓度 (ICTP)，并将在给药前、观察剂量后 2、4 和 8 小时测定未结合的 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（主任：CV Fletcher）实时进行。 这些密集的药代动力学特征将允许对药代动力学参数进行非房室分析，包括 PI 的浓度时间曲线下面积 (AUC)。 如果 AUC 值低于历史群体第 25 个百分位和/或最低浓度 (Cmin) 低于第 50 个百分位，将建议在密集药代动力学访视后两周内调整 PI 成分的剂量。 在推荐 PI 剂量（无论是否调整）后大约两周，将进行另一次短期研究访问，以评估 PI 的谷结合和未结合浓度，并收集血液进行 ICTP NRTI 定量。 这些短期研究访问将在妊娠晚期强化药代动力学访问后再次重复。 最后，对于那些继续接受抗逆转录病毒治疗的妇女，将在产后两周收集抗逆转录病毒药物的产后血浆谷浓度。 将再次收集血液用于 ICTP 定量和产后未结合的 PI 浓度。 药代动力学分析的一个重要组成部分包括依从性咨询。 研究人员将在预定的研究访问期间讨论每位研究参与者的依从性，包括讨论必要的饮食要求，以获得充分的吸收并减少患者正在接受的每种药物的不良反应。 这项研究的重要性在于，它将生成 625 mg 奈非那韦片剂配方和 200/50 mg 洛匹那韦/利托那韦片剂配方的血浆结合和非结合药代动力学数据。 此外，还将首次在怀孕期间测量 ICTP NRTI 水平。 它还将提供有关孕期奈非那韦和洛匹那韦/利托那韦药代动力学指导剂量调整有效性的信息，并将允许对从妊娠第二个月开始一直到产后期的个体药代动力学参数进行纵向描述。