A5223-SEX DIFFERENCES IN LOPINAVIR/RITONAVIR PHARMACOKINETICS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。设计：将对78名可评估受试者(39名男性和39名女性)在服用上午剂量的洛比那韦/利托那韦(LPV/RTV)之前和之后12小时内获得的血浆样本进行药代动力学(PK)评估，这是他们抗逆转录病毒治疗的一部分。持续时间：将在PK访问前30天内进行筛查访问。在确认合格后，受试者将返回注册/进入访问以登记加入研究，并将被给予48小时的药物日记以完成。受试者将被要求在普通临床研究中心(GCRC)或类似的研究诊所花费大约13个小时进行密集的PK血液采样。人群：78名艾滋病毒感染者，39名男性和39名女性，年龄18岁，目前正在接受LPV/RTV(洛比那韦400毫克/利托那韦100毫克，每天2次)加以下一种或多种药物的治疗：核苷逆转录酶抑制剂(NRTI)、替诺福韦(一种核苷酸RTI)和恩福韦肽(一种融合抑制剂)。受试者必须在筛查前至少14天接受相同的方案。分层：按种族/民族分层的受试者。方案：受试者将接受LPV/RTV和以下一种或多种药物的治疗：NRTIs、替诺福韦(TDF)和恩福韦肽(ENF)。这项研究不会提供这些药物。1.0假设和研究目标1.1假设服用相似剂量LPV/RTV的女性LPV药物水平高于男性。1.2初步目的比较目前接受LPV/RTV相似剂量的HIV-1感染男性和女性LPV的PK参数、LPV浓度-时间曲线下面积(AUC)。1.3次级目标1.3.1比较目前正在接受类似剂量LPV/RTV的HIV-1感染男性和女性之间的PK参数：最大浓度(Cmax)、剂量后12小时浓度(C12h)和LPV的口服表观清除量(CL/F)。1.3.2评估种族/民族对HIV-1感染者LPV PK参数的影响。1.3.3确定与LPV的AUC差异相关的因素。感兴趣的协变量包括年龄、体重、体重指数(BMI)和TDF的使用。1.3.4研究LPV PK参数与LPV/RTV中毒的自述体征和症状的关系。1.3.5评估上述LPV PK参数与胃肠道症状和体征的关系。胃肠道症状定义为3级恶心、呕吐、腹泻、腹痛和腹胀。1.3.6评估感染HIV-1的男性和女性在利托那韦(RTV)PK参数上的差异。这项研究将观察服用卡莱特拉韦(也称为洛匹那韦/利托那韦)的男性和女性的血液中的药物水平，看看他们是否不同。这项研究还将试图找出年龄、体重、种族/民族和其他药物等因素如何影响这些药物水平的结果。最近的科学研究表明，越来越多的女性感染了艾滋病毒。据认为，全世界感染艾滋病毒/艾滋病的人中有一半是妇女。然而，大多数最初关于用于治疗艾滋病毒感染的药物的安全性和有效性的研究并没有包括很多女性。最近的研究表明，艾滋病毒药物对男性和女性的影响可能不同。A5223的药理学研究的预期结果是提供对LPV/RTV的PK特征的估计，以评估这些参数在男性和女性之间是否不同。

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. DESIGN: Pharmacokinetic (PK) evaluations will be performed on plasma samples obtained prior to and up to 12 hours after the administration of the morning dose of lopinavir/ritonavir (LPV/RTV) in 78 evaluable subjects (39 men and 39 women) currently managed on LPV/RTV as part of their antiretroviral regimen. DURATION: A screening visit will occur within 30 days prior to the PK visit. Upon confirmation of eligibility, subjects will return for a registration/entry visit to enroll into the study and will be given a 48 hour medication diary to complete. Subjects will be required to spend approximately 13 hours at a general clinical research center (GCRC) or a similar research clinic setting for the intensive PK blood sampling. POPULATION: Seventy-eight HIV-infected subjects, 39 men and 39 women, age 18 years currently receiving LPV/RTV (lopinavir 400 mg/ritonavir 100 mg po bid) plus one or more of the following: nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir (a nucleotide RTI), and enfuvirtide (a fusion inhibitor). Subjects must be on the same regimen for at least 14 days prior to screening. STRATIFICATION: Subjects to be stratified by race/ethnicity. REGIMEN: Subjects will be on LPV/RTV and one or more of the following: NRTIs, tenofovir (TDF), and enfuvirtide (ENF). These drugs will not be provided by this study. 1.0 HYPOTHESIS AND STUDY OBJECTIVES 1.1 Hypothesis Women achieve higher LPV drug levels than do men on similar doses of LPV/RTV. 1.2 Primary Objective To compare the PK parameter, area under the concentration-time curve (AUC) of LPV between HIV-1-infected men and women currently receiving similar doses of LPV/RTV. 1.3 Secondary Objectives 1.3.1 To compare the PK parameters: the maximum concentration (Cmax), 12 hour post- dose concentration (C12h), and the apparent oral clearance (CL/F) of LPV between HIV-1-infected men and women currently receiving similar doses of LPV/RTV. 1.3.2 To evaluate the effect of race/ethnicity on the PK parameters of LPV in HIV-1- infected subjects. 1.3.3 To identify factors associated with differences in the AUC of LPV. Covariates of interest include age, weight, body mass index (BMI), and the use of TDF. 1.3.4 To examine the relationship of LPV PK parameters with self-reported signs and symptoms of LPV/RTV toxicity. 1.3.5 To evaluate the association between the LPV PK parameters listed above and gastrointestinal signs and symptoms. Gastrointestinal signs and symptoms are defined as Grade 3 nausea, vomiting, diarrhea, abdominal pain, and bloating. 1.3.6 To evaluate differences in ritonavir (RTV) PK parameters between HIV-1- infected men and women. This study will look at drug levels in the blood in both men and women taking Kaletra¿ (also known as lopinavir/ritonavir) to see if they are different. This study will also try to find out how factors such as age, weight, race/ethnicity, and other medications may affect these drug level results. Recent scientific studies have suggested that more and more women are being infected with the HIV virus. It is thought that half of all the people in the world living with HIV/AIDS are women. However, most of the initial research studies on the safety and effectiveness of drugs used for treatment of HIV infection did not include a lot of women. Recent research suggests that HIV medications may affect men and women differently. The anticipated outcome of the pharmacologic studies for A5223 is to provide estimates of the PK characteristics of LPV/RTV to assess whether these parameters are different between men and women.