INTEGRATE/PHARMACOKINETIC/ANTIRETROVIRUS RESISTANCE TEST

描述（由申请方提供）：本申请描述了一种整合药代动力学（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，用于其治疗经验丰富的HIV感染患者的挽救治疗。从文献中收集基于多种双重蛋白酶抑制剂（PI）或非核苷类似物（NNRTI）方案的PK参数。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。这提供了在平均患者人群中可以预期的宽范围的谷水平。PI或NNRTI的IC 50针对血浆蛋白结合进行校正，并与模拟谷水平的范围进行比较（克雷格）。在使用这种称为概率估计的方法时，可以确定每种药物达到高于蛋白结合校正IC 50（PBICs 0）的谷水平的概率。该方法根据达到所需血药浓度的可能性对每种可能的方案进行排序。该方法直接适用于临床，并且不需要测量药物水平。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。病毒耐药性是一个连续体;病毒敏感性的某些倍数变化并不一定使药物失活，必须考虑患者体内可达到的药物浓度。本申请的具体目的是：1）通过将基线时每名受试者达到高于PBIC 95的PI谷浓度的估计概率与随后测量的实际IQ相关联，前瞻性验证概率估计方法，该实际IQ是在接受基于概率估计方法选择的抗逆转录病毒治疗方案时，在第4周进行密集药代动力学评价得出的;和2）通过将60名具有中等水平耐药性的受试者纳入两个随机化组，在前瞻性的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加药物药代动力学，以供临床医生指导。所有受试者将在第4周接受强化PK评价，并每4周一次随访，持续16周，以评估短期病毒学应答。 这项工作的长期目标是：（1）允许将这些观察结果扩展到更大的、对照良好的临床试验中，并根据此处生成的I期研究结果优化样本量计算;（2）最终将这些结果扩展到治疗经验较少的患者中，以证明其广泛的临床适用性。

DESCRIPTION (provided by applicant): This application describes a method of integrating pharrnacokinetic (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 parameters from multiple dual protease inhibitor (PI)-based or non-nucleoside analog (NNRTI) regimens were collected from the literature. PK models with built-in variability were created for each regimen and used to simulate 100 concentration-time curves for each regimen. This provides a wide range of trough levels that can be expected in the average patient population. The IC50 for a PI or NNRTI is corrected for plasma protein binding and compared with the range of simulated trough levels (Craig). In using this approach, called Probability Estimations, it is possible to determine the probability of achieving trough levels above the protein-binding corrected IC50 (PBICs0) for each drug. This method ranks each possible regimen based on the likelihood of achieving the desired plasma concentrations. This approach is directly applicable to the clinic, and does not require measurement of drug levels. The hypothesis is that integration of PK and phenotypic information maximizes the benefit of antiretroviral therapy in the management of treatment-experienced subjects. Viral drug resistance is a continuum; a certain fold-change in virus susceptibility does not necessitate a drug will be inactive and achievable drug concentrations in the patient must be considered. 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 PBIC95 for each participant at baseline with their subsequently measured actual IQ derived from an intensive pharmacokinetic evaluation at week 4 while receiving an antiretroviral regimen selected based on the Probability Estimations approach; 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 phenotypie test for clinician guidance, the other arm will use the Probability Estimations approach that inherently includes phenotyping plus drug pharmacokinetics for clinician guidance. All subjects will undergo an intensive PK evaluation at week 4, and followed every 4 weeks for 16 weeks to assess short-term virologic response. The long-term objectives of this work are: (1) to allow expansion of these observations into a larger, well-controlled clinical trial with optimized sample size calculations based on the phase I study results generated here; and (2) to ultimately expand these findings into less treatment-experienced patients to demonstrate its widespread clinical applicability.