A5223-SEX DIFFERENCES IN LOPINAVIR/RITONAVIR PHARMACOKINETICS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。设计：将对78名可评估受试者（39名男性和39名女性）在给予洛匹那韦/利托那韦（LPV/RTV）早晨剂量之前和12小时后获得的血浆样本进行药代动力学（PK）评估，这些受试者目前使用LPV/RTV作为抗逆转录病毒治疗方案的一部分。持续时间：筛选访问将在PK访问前30天内进行。在确认合格后，受试者将返回进行注册/入组访问以参加研究，并将获得48小时用药日记。受试者将被要求在普通临床研究中心（GCRC）或类似的研究诊所环境中花费大约13小时进行密集的PK血液采样。人群：78名hiv感染者，39名男性和39名女性，年龄18岁，目前正在接受LPV/RTV（洛匹那韦400mg /利托那韦100mg / bid）加一种或多种以下药物：核苷类逆转录酶抑制剂（NRTIs）、替诺福韦（核苷酸RTI）和恩福韦肽（融合抑制剂）。受试者必须在筛查前至少14天使用相同的方案。分层：受试者按种族/民族分层。方案：受试者将接受LPV/RTV和以下一种或多种治疗：NRTIs、替诺福韦（TDF）和恩福韦肽（ENF）。本研究不提供这些药物。假设在相同LPV/RTV剂量下，女性的LPV药物水平高于男性。1.2主要目的比较目前接受相同剂量LPV/RTV的hiv -1感染男性和女性LPV的PK参数、浓度-时间曲线下面积（AUC）。1.3.1比较PK参数：目前接受相似剂量LPV/RTV的hiv -1感染男性和女性LPV的最大浓度（Cmax）、给药后12小时浓度（C12h）和口服表观清除率（CL/F）。1.3.2评价人种/民族对HIV-1感染者LPV PK参数的影响。1.3.3确定与LPV AUC差异相关的因素。相关协变量包括年龄、体重、身体质量指数（BMI）和TDF的使用。1.3.4检验LPV PK参数与自述LPV/RTV毒性体征和症状的关系。1.3.5评价上述LPV PK参数与胃肠道体征症状的相关性。胃肠道体征和症状定义为3级恶心、呕吐、腹泻、腹痛和腹胀。1.3.6评价HIV-1感染男性和女性利托那韦（RTV） PK参数的差异。这项研究将观察服用Kaletra¿（也称为洛匹那韦/利托那韦）的男性和女性血液中的药物水平，看看他们是否有不同。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，越来越多的妇女感染艾滋病毒。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，大多数关于用于治疗艾滋病毒感染的药物的安全性和有效性的初步研究并没有包括很多妇女。最近的研究表明，艾滋病药物对男性和女性的影响可能不同。A5223药理学研究的预期结果是提供LPV/RTV的PK特性的估计，以评估这些参数在男性和女性之间是否存在差异。

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.