ANTIRETROVIRAL PHARMACOLOGY IN THE GENITAL TRACT

描述(由申请人提供)：了解生殖道(GT)中的抗逆转录病毒(ARV)药理学至关重要，因为这些疗法有可能通过减少艾滋病毒RNA和降低感染者的传染性，或通过暴露前或暴露后的预防措施来减少艾滋病毒的性传播。GT中低浓度的抗逆转录病毒药物可能会使暴露前和暴露后的预防方案无效，并可能导致出现抗药性艾滋病毒突变，从而影响艾滋病毒向其他人的传播，并导致个别患者的抗逆转录病毒失败。 这项建议研究了抗逆转录病毒药物在生殖道中的药代动力学/药效学关系和病毒学反应。提出了三个具体目标。在具体目标1中，将测定14种ARV在直接吸入的女性GT分泌物中的完整药代动力学。在具体目标2中，我们建议通过测量来自血液和GT分泌物的男性和女性单个核细胞中核苷类似物一、二和三磷酸的浓度来评估GT的细胞内药理学。在具体目标3中，将通过建立药代动力学/药效学和统计学模型来评估女性生殖道中艾滋病毒的分区，以评估女性生殖道中的病毒学应答率与血浆艾滋病毒RNA、血浆中的ARV暴露以及GT中的ARV暴露之间的关系。 申请书中描述的研究项目构成了药学院助理教授Angela Kashuba博士五年职业发展计划的核心。她的导师迈伦·科恩博士是一名知名的艾滋病毒调查员，是医学院传染病科(ID)主任和北卡罗来纳大学传染病中心(CFID)主任。她的合作导师金·布劳威尔博士在药物处置和作用方面的临床研究的设计、实施和分析方面拥有丰富的经验。她的合作导师理查德·蒂德韦尔博士在过去10年里对治疗艾滋病相关机会性感染的新药物的设计、测试和开发进行了广泛的研究。他们提出了一种教学和临床研究相结合的经验，利用北卡罗来纳大学CFAR和CFID以及北卡罗来纳大学综合临床研究中心的资源，培养卡舒巴博士在评估GT中ARV药代动力学/药效关系方面的研究技能。他们召集了一个精心挑选的合作者和顾问小组，以协助这些研究项目和卡舒巴博士的职业发展。 这个项目的长期目标是：1)通过在男性和女性GT中促进抗逆转录病毒药理学和病毒学的科学来影响艾滋病毒的传播，以便最佳地选择抗逆转录病毒治疗的有效组合，以及2)根据临床药理学研究的职业发展申请人在统计学、流行病学、药代动力学/动力学建模和药理学分析方法方面的技能。

DESCRIPTION (provided by applicant): Understanding antiretroviral (ARV) pharmacology in the genital tract (GT) is critically important, as these therapies have the potential to decrease sexual transmission of HIV by reducing HIV RNA and rendering the infected person less infectious, or by pre- or post-exposure prophylaxis. Low concentrations of ARVs in the GT may render pre-and post-exposure prophylaxis regimens ineffective, and may result in the emergence of drug resistant HIV mutations that could impact HIV transmission to others, and result in antiretroviral failure in an individual patient. This proposal examines the pharmacokinetic/pharmacodynamic relationships of ARVs and virologic response in the genital tract. Three Specific Aims are proposed. In Specific Aim 1, the complete pharmacokinetics of 14 ARVs in directly-aspirated female GT secretions will be determined. In Specific Aim 2, we propose to evaluate GT intracellular pharmacology by measuring nucleoside analogue mono, di, and triphosphate concentrations in male and female mononuclear cells derived from blood and GT secretions. In Specific Aim 3, HIV compartmentalization in the female genital tract will be assessed by developing pharmacokinetic/pharmacodynamic and statistical models to evaluate the relationship between virologic response rates in the female GT, and blood plasma HIV RNA, ARV exposure in blood plasma, and ARV exposure in the GT. The research projects described in this application form the core of a 5-year career development plan for Dr. Angela Kashuba, an assistant professor in the School of Pharmacy. Her mentor, Dr. Myron Cohen is an established HIV investigator, is Chief of the Division of Infectious Diseases (ID) in the School of Medicine, and Director of the UNC Center for Infectious Diseases (CFID). Her co-mentor Dr. Kim Brouwer has significant experience in the design, conduct, and analysis of clinical studies focusing on drug disposition and action. Her co-mentor Dr. Richard Tidwell has conducted extensive research in the design, testing and development of new agents for treatment of AIDS-associated opportunistic infections over the last 10 years. They propose a combined didactic and clinical research experience, utilizing the resources of the UNC CFAR and CFID, and the UNC General Clinical Research Center to foster Dr. Kashuba's research skills in evaluating ARV pharmacokinetic/pharmacodynamic relationships in the GT. They have assembled a carefully selected group of collaborators and advisors to assist in these research projects and Dr. Kashuba's career development. The long-term objectives of this project are to: 1) impact HIV transmission by advancing the science of ARV pharmacology and virology in the male and female GT in order to optimally chose effective combinations of antiretroviral therapies, and 2) to develop the applicant's skills in statistical, epidemiological, pharmacokinetic/dynamic modeling, and analytical methods in pharmacology pursuant to a career in clinical pharmacology research.