Cellular pharmacology of tenofovir and emtricitabine for HIV prophylaxis

描述（由申请人提供）：替诺福韦（TFV）和恩曲他滨（FTC）正在研究联合用于HIV预防。TFV和FTC属于核苷类似物逆转录酶抑制剂（NRTl）药物类别，其在患者中经历顺序磷酸化为细胞内三磷酸合成代谢物。NRT 1的药理活性取决于三磷酸，其抑制HIV逆转录酶以引起药理作用。磷酸化的拮抗剂被电离并捕获在细胞内，这导致与血浆中的母体药物相比不同的药代动力学。患者中NRT 1的给药由活性三磷酸的细胞内谱指导，这证明了NRT 1细胞药理学信息对人类健康的重要性。HIV预防是TFV和FTC在新患者群体（HIV阴性者）中的新用途。需要细胞药理学数据来支持和指导这一新用途，但尚未生成此信息。从正在接受慢性HIV感染治疗的HIV阳性患者中推断细胞内信息是不可接受的，因为这是一个不同的患者组和治疗方案。事实上，患者组具有不同的细胞活化状态，与慢性HIV治疗相比，预防存在不同的药效学考虑。本文拟定的研究将提供与HIV预防相关的细胞药理学数据。主要目标是：表征和比较HIV阴性与HIV阳性成人中TFV和FTC的细胞内谱;确定HIV阴性成人中细胞内TFV和FTC的预防阈值;开发细胞内TFV和FTC的综合药代动力学模型，以预测预防作用的最佳剂量、起效时间和持续时间;并评估TFV的药理学谱是否包括体内嘌呤核苷磷酸化酶抑制。该申请实现了我们的长期目标，即通过基于患者中TFV和FTC细胞药理学的合理给药策略，促进TFV和FTC在HIV预防和治疗中的最佳使用。

DESCRIPTION (provided by applicant): Tenofovir (TFV) and emtricitabine (FTC) are under study in combination for HIV prophylaxis. TFV and FTC belong to the nucleoside analog reverse transcriptase inhibitors (NRTls) drug class, which undergoes sequential phosphorylation in patients to the intracellular triphosphate anabolite. The pharmacologic activity of NRTls depends on the triphosphate, which inhibits HIV reverse transcriptase to elicit pharmacologic effect. The phosphorylated anabolites are ionized and trapped within cells, which leads to differing pharmacokinetics compared with the parent drug in plasma. The dosing of NRTls in patients is guided by the intracellular profile of the active triphosphates, which demonstrates the human health importance of NRTl cellular pharmacology information. HIV prophylaxis is a new use for TFV and FTC in a new patient group (HIV-negative persons). Cellular pharmacology data are needed to support and guide this new use, but this information has not been generated. It is not acceptable to extrapolate intracellular information from HIV positive patients under treatment for chronic HIV-infection because this is a different patient group and treatment scenario. In fact, the patient groups have different cellular activation states and different pharmacodynamic considerations exist for prophylaxis compared with treatment of chronic HIV. The studies proposed herein will provide cellular pharmacology data relevant to HIV prophylaxis. The main goals are: to characterize and compare the intracellular profiles of TFV and FTC in HIV-negative versus HIV-positive adults; to identify a prophylactic threshold for intracellular TFV and FTC in HIV-negative adults; to develop a comprehensive pharmacokinetic model for intracellular TFV and FTC to predict the optimal dose and onset and duration of prophylactic action; and to evaluate whether the pharmacologic spectrum of TFV includes inhibition of purine nucleoside phosphorylase in vivo. The application addresses our long term goal to promote the optimal use of TFV and FTC for HIV prevention and treatment through rational dosing strategies founded on TFV and FTC cellular pharmacology in patients.