Accelerating to the Cure: A Novel IVIVE Model for Advancing HIV Eradication Strategies

项目摘要 问题：尽管在过去的20年里，艾滋病毒治疗取得了显着的进步， 艾滋病毒感染者（PLWH）仍然需要终身坚持昂贵的、多种药物的、每日给药方案。斯塔克 这种具有挑战性的治疗方式的现实是，美国近50%的PLWH不是病毒学上的， 抑制迫切需要一种实现持续、无药物缓解的艾滋病毒治疗方法。的 这种治疗的主要障碍是潜在的水库，一个长寿命的，潜伏感染细胞的子集， 复制能力病毒。 研究性治疗策略寻求通过配对激活然后清除（靶向和清除）该储库 潜伏期逆转剂（LRA）与免疫调节剂。超过50种小分子，横跨7个机械类别 被认为是潜在的LRA。然而，在过去十年的研究中，没有一个人能超越早期阶段。 由于不可接受的毒性或疗效不足而导致临床开发失败。药物的关键成分 在LRA开发中被广泛忽视的一个开发是PK/PD指标的识别 (e.g. Cmax/EC50）。这些目标对于优化剂量以实现 在治疗窗内的浓度曲线。 总体目标：通过利用PK/PD建模和模拟的预测能力， LRA从实验室到患者的进步。我们已经开发出一种从体外到体内 在一个实施方案中，本发明提供了一种外推（IVIVE）系统，其结合了潜伏期的细胞模型并且可以模拟人PK。我们将 使用该系统来识别用于潜伏期逆转的PK/PD指数。 研究设计：我们从3种机制类别中选择了6种有希望的LRA，使用我们的新型IVIVE进行评估 模型我们根据已发表的人体PK数据确定了这些LRA，并对现有或 PLWH的预期临床研究结果。在AIM 1中，我们将使用已建立的延迟细胞模型， 通过拟合在4-log浓度范围内表征LRA浓度与潜伏期逆转关系 S形Emax模型来估计每个LRA的以下参数：EC25、EC 50、EC 75和EC 90。在AIM 2中 我们将通过模拟每种LRA的人体PK特征来确定HIV潜伏期逆转的PK/PD指标， 进行剂量分级研究。我们将为12种PK/PD指标组合拟合S形Emax模型 (Cmax/IC 50、AUC/EC 90、时间> EC 75等）与HIV潜伏期逆转，并确定最佳拟合模型。我们将 通过交叉引用我们的预测与临床试验结果来验证我们的模型（在可能的情况下）。 预期结果：这项工作将指导广泛LRA组合的剂量优化，并协助选择 动物和人类研究的有效剂量。通过临床验证，我们将建立我们的新IVIVE模型 作为一种新的范例，以加快艾滋病毒治疗战略的发展。

Project Summary Problem: Despite remarkable advances in HIV treatment over the last 2 decades, viral suppression in people living with HIV (PLWH) still requires lifelong adherence to expensive, multidrug, daily dosing regimens. The stark reality of this challenging treatment modality is that almost 50% of PLWH in the US are not virologically suppressed. An HIV cure that achieves sustained, medication-free remission is desperately needed. The main obstacle to this cure is the latent reservoir, a subset of long-lived, latently infected cells harboring replication-competent virus. Investigational cure strategies seek to activate then clear (Target and Clear) this reservoir by pairing latency-reversing agents (LRAs) with immunomodulators. Over 50 small molecules across 7 mechanistic classes have been identified as potential LRAs. Yet in the last decade of research, none have advanced past early stages of clinical development due to unacceptable toxicity or inadequate efficacy. A critical component of drug development that has been widely overlooked in the development of LRAs, is identification of PK/PD indices (e.g. Cmax/EC50) associated with drug effect. These targets are essential for optimizing doses to achieve a concentration profile within the therapeutic window. Overarching Goal: By leveraging the predictive power of PK/PD modeling and simulation, we aim to accelerate the advancement of LRAs from the Laboratory to the Patient. We have developed an in vitro to in vivo extrapolation (IVIVE) system that incorporates a cellular model of latency and can simulate human PK. We will employ this system to identify PK/PD indices for latency reversal. Study Design: We have selected 6 promising LRAs from 3 mechanistic classes to assess using our novel IVIVE model. We identified these LRAs based on published human PK data, and prioritized LRAs with existing or anticipated clinical study results in PLWH. In AIM 1 we will use established cellular models of latency to characterize the LRA concentration vs latency reversal relationship across a 4-log concentration range by fitting sigmoid Emax models to estimate the following parameters for each LRA: EC25, EC50, EC75, and EC90. In AIM 2 we will identify PK/PD indices for HIV latency reversal by simulating the human PK profile for each LRA and conducting dose fractionation studies. We will fit sigmoid Emax models for 12 combinations of PK/PD indices (Cmax/IC50, AUC/EC90, Time>EC75, etc.) vs HIV latency reversal and determine the best fitting models. We will validate our model (where possible) by cross-referencing our predictions with clinical trial results. Anticipated Outcome: This work will guide dose optimization for a broad portfolio of LRAs and assist in selecting effective doses for animal and human studies. Through clinical validation, we will establish our novel IVIVE model as a new paradigm to accelerate the development of HIV cure strategies.