PHARMACOKINETICS & ANTIRETROVIRUS RESISTANCE TESTING

药代动力学

• 批准号: 6840628
• 负责人: Edward P Acosta
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6840628
• 关键词: AIDS; AIDS therapy; HIV infections; Retroviridae; antiAIDS agent; antiviral agents; blood chemistry; clinical research; data collection methodology /evaluation; drug resistance; drug screening /evaluation; high performance liquid chromatography; human therapy evaluation; outcomes research; patient care management; patient care planning; pharmacokinetics; prognosis; statistics /biometry; therapy design /development; virus load

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.

描述（由申请人提供）：本申请描述了一种整合Pharrnacokinetic（PK）和病毒表型药物敏感性（IC50）信息的方法，以帮助临床医生选择最佳治疗治疗治疗治疗治疗的HIV受HIV感染患者。从文献中收集了来自多个双重蛋白酶抑制剂（PI）类似物（NNRTI）方案的PK参数。为每种方案创建了具有内置可变性的PK模型，并用于模拟每种方案的100个浓度时间曲线。这提供了广泛的低谷水平，这些水平可以预期在普通患者人群中。 PI或NNRTI的IC50通过血浆蛋白结合进行了校正，并与模拟的槽水平（CRAIG）进行了比较。在使用这种方法（称为概率估计）时，可以确定每种药物的蛋白质结合校正IC50（PBICS0）以上的谷水平水平的概率。此方法根据达到所需的血浆浓度的可能性对每种可能的方案进行排名。这种方法直接适用于诊所，不需要测量药物水平。假设是，PK和表型信息的整合使抗逆转录病毒疗法在治疗经验受试者管理中的好处。病毒耐药性是连续性；在病毒易感性中，某些折叠变化不必在患者中不需要药物不活跃，并且必须考虑可实现的药物浓度。该应用的具体目的是：1）通过将基线时每个参与者的PI浓度高于PBIC95的估计概率与随后测量的实际智商相关联，该方法是通过在第4周接受强制性药物评估的实际智商来实现的，同时在接受抗逆转录病毒方案估计性估计性估计的方法中，在基线时测量的实际智商估计了PBIC95的概率，从而验证了概率估计方法：1）。 2）通过将60名中度耐药性的受试者招募到两个随机臂中，以评估一项前瞻性，16周的“概念证明”试点研究中的短期病毒学反应。一只臂将使用其随后的打捞方案，使用表型测试进行临床指导，另一只臂将使用概率估计方法固有的概率估计方法，该方法固有地包括表型和药物药代动力学用于临床指导。所有受试者将在第4周进行密集的PK评估，并每4周遵循16周的时间来评估短期病毒学反应。 这项工作的长期目标是：（1）允许将这些观察结果扩展为一个基于此处产生的I期研究结果的优化样本量计算的更大，控制良好的临床试验； （2）最终将这些发现扩展到经验较低的患者中，以证明其广泛的临床适用性。