INTEGRATING PHARMACOKINETICS AND ANTIRETROVIRAL RESISTANCE TESTING

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本申请描述了一种整合药物代谢动力学（PK）和病毒表型药物敏感性（IC 50）信息的方法，以帮助临床医生选择最佳方案，用于治疗有治疗经验的HIV感染患者的挽救治疗。为每个方案创建具有内置变异性的PK模型，并用于模拟每个方案的100个浓度-时间曲线。PI或NNRTI的IC 50针对血浆蛋白结合进行校正，并与模拟谷浓度范围（Cmin）进行比较。假设PK和表型信息的整合使抗逆转录病毒治疗在治疗经验受试者管理中的获益最大化。本申请的具体目的是：1）通过将基线时每例受试者达到高于PB IC 95的PI谷浓度的估计概率相关联，前瞻性验证概率估计方法，2）通过将60例中度耐药受试者入组两个随机化组，在前瞻性16周“概念验证”初步研究中评估短期病毒学应答。一组将使用表型检测选择后续挽救治疗方案，以供临床医生指导，另一组将使用概率估计方法，该方法固有地包括表型分析和药物药代动力学，以供临床医生指导。这项工作的长期目标是：（1）将这些观察结果扩展到更大的、对照良好的临床试验中;（2）将这些发现扩展到治疗经验较少的患者中。

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. This application describes a method of integrating pharmacolunetic (PK) and viral phenotypic drug susceptibility (IC50) information to assist clinicians in choosing optimal regimens for salvage therapy of their treatment-experienced HIV-infected patients. PK models with built-in variability were created for each regimen and used to simulate 100 concentration-time curves for each regimen. The IC50 for a PI or NNRTI is corrected for plasma protein binding and compared with the range of simulated trough levels (Cmin). The hypothesis is that integration of PK and phenotypic information maximizes the benefit of antiretroviral therapy in the management of treatment experienced subjects. The specific aims of this application are: 1) to prospectively validate the Probability Estimations method by correlating the estimated probability of achieving PI trough concentrations above the PB IC95 for each participant at baseline, and 2) to assess short-term virologic response in a prospective, 16-week "proof-of-concept" pilot study by enrolling 60 subjects with moderate-level drug resistance into two randomized arms. One arm will have their subsequent salvage regimen chosen using a phenotypic test for clinician guidance, the other arm will use the Probability Estimations approach that inherently includes phenotyping plus drug pharmacokinetics for clinician guidance. The long-term objectives of this work are: (1) to allow expansion of these observations into a larger, well-controlled clinical trial; and (2) to expand these findings into less treatment-experienced patients.