Cellular pharmacology of tenofovir and emtricitabine for HIV prophylaxis

描述（由申请人提供）：替诺福韦（TNV）和恩曲他滨（FTC）通常是安全、有效的，并表现出吸引人的药代动力学特性，因为药理活性磷酸化部分在HIV感染患者的单核细胞中表现出长半衰期。这些有利的特点提供了一个动力，以评估TNV和FTC在一个新的临床环境中，暴露前HIV预防HIV阴性的人（PreP）。目前正在进行几项PreP的大型III期临床试验。然而，没有研究比较TNV/FTC在HIV阴性与HIV感染者中的细胞药理学。如果不了解这些信息，就不可能对这种新适应症做出最明智的剂量和给药决定。该申请提出了一个计划期，以准备一项II期临床研究，以确定和比较TNV和FTC在HIV血清阴性与HIV血清阳性成人中的细胞药理学。规划期间的两个目标是：为进行第二阶段研究充分制定一份全面的业务手册，并向所有必要的管理机构提交完整的文件。临床的总体假设 研究表明，HIV感染显著影响TNV的细胞药理学， 联邦贸易委员会为了说明，细胞内TNV-磷酸盐，我们研究的重点，是3倍高，并持续存在 在体外，静息单核细胞比活化单核细胞长3倍。我们建议这些体外 这些发现与人类有关，因为HIV感染显著提高了 单核细胞和体内组织。我们的研究将阐明，根据艾滋病毒血清状态， 细胞内TNV/FTC升高至稳态（与作用开始相关）， 消除率（与漏服剂量、给药中断和潜在耐药窗口相关）。 我们还将研究TNV在体内抑制嘌呤核苷磷酸化酶（PNP）的潜力。 这一目标的基本原理来自体外研究，该研究表明，TNV-单磷酸 有效抑制PNP介导的去羟肌苷（ddI）分解。然而，目前尚不清楚TNV 导致体内普遍的PNP抑制，这是基础知识中的一个根本空白。间接 有证据表明，TNV确实在体内引起了广泛的PNP抑制，因为TNV是 与非预期的T淋巴细胞减少相关，在其他研究中，与低尿酸血症相关。我们的研究将 量化，第一次，全身PNP抑制TNV在体内。如果我们的假设是 正确的，TNV-磷酸盐在HIV阴性者的“静息细胞状态”中会更高， 与HIV感染者相比，这些人的广义PNP抑制将更明显 人士在第二阶段研究中了解到的新信息将直接解决最重要的问题， 以及适用于PreP适应症的临床相关药理学考虑。

DESCRIPTION (provided by applicant): Tenofovir (TNV) and emtricitabine (FTC) are generally safe, effective, and exhibit appealing pharmacokinetic properties, as the pharmacologically-active phosphorylated moieties exhibit a long half-life in mononuclear cells of HIV-infected patients. These favorable characteristics provide an impetus to evaluate TNV and FTC in a new clinical setting, pre-exposure HIV prophylaxis in HIVnegative persons (PreP). Several large phase-III clinical trials for PreP are currently underway. However, no studies have compared the cellular pharmacology of TNV/FTC in HIV-negative versus HIV-infected persons. Without this knowledge, it is impossible to make the most informed dose and dosing decisions for this new indication. This application proposes a planning period in preparation for a phase II clinical research study to define and compare the cellular pharmacology of TNV and FTC in HIV-seronegative versus HIV-seropositive adults. The two goals of the planning period are: To fully develop a comprehensive manual of operations for the conduct of the phase II study and to submit complete documentation to all necessary regulatory agencies. The overall hypothesis for clinical research study is that HIV-infection significantly influences the cellular pharmacology of TNV and FTC. To illustrate, intracellular TNV-phosphates, the focus of our studies, are 3-fold higher and persist for 3-fold longer in resting versus activated mononuclear cells in vitro. We propose that these in vitro findings are relevant to humans because HIV infection significantly elevates the activation-state of mononuclear cells and tissues in vivo. Our study will elucidate, according to HIV serostatus, the rate that intracellular TNV/FTC rise to steady-state (relevant for the onset of action) and the terminal elimination rate (relevant for missed doses, dosing interruptions, and potential window for resistance). We will also investigate the potential for TNV to inhibit purine nucleoside phosphorylase (PNP) in vivo. The rationale for this aim arises from an in vitro study which showed that TNV-monophosphate potently inhibited PNP-mediated didanosine (ddI) breakdown. It is not known, however, whether TNV causes a generalized PNP inhibition in vivo, which is a fundamental gap in basic knowledge. Indirect evidence makes a case that TNV does in fact cause a generalized PNP inhibition in vivo, as TNV is associated with unexpected T-lymphocytopenia and, in other studies, hypouricemia. Our study will quantify, for the first time, generalized PNP inhibition by TNV in vivo. If our overall hypothesis is correct, TNV-phosphates will be higher in the "resting cell-state" of HIV negative persons and generalized PNP inhibition will be more pronounced in these persons compared with HIV-infected persons. The new information learned in this phase II study will directly address the most important and clinically relevant pharmacologic considerations applicable to the indication of PreP.