Subtopic 1 : Population pharmacokinetic and pharmacodynamic, dose-toxicity modleing and simulation for narrow therapeutic index (NTI) drugs

项目摘要 联邦法规已经将窄治疗指数（NTI）药物定义为具有更少的 半数致死剂量和半数有效剂量的差异小于2倍，或 血液中最低毒性浓度和最低有效浓度的差异。 然而，目前还没有一套明确的客观的理论来界定非关税壁垒。有一个明确的客观定义， 从监管和行业的角度来看，这是非常重要的。 CFR暗示在生物等效性（BE）评价期间将NTI视为一个因素。有几 出版物强调了如果在品牌和 NTI药物的通用形式。药物科学咨询委员会（ACPS） 在2010年4月的会议上，FDA建议制定一份NTI药物清单， 标准和目前的BE标准对于NTI药物是不够的。这突出了以下方面的重要性： 制定准确、客观的标准，评估NTI药物的BE。 本研究的目的是利用药代动力学（PK）、药效学（PD） 和PK/PD关系的陡峭度，以提出定量指标来识别NTI药物并提出BE 标准，以更好地了解品牌和仿制药之间的区别。模拟以及 NTI药物的已发表文献信息将用于分析。质量方面，包括 疾病的严重程度和不良事件的可逆性将被纳入决策树。的 将通过应用于批准的NTI和非NTI，评价决策树的灵敏度和特异性 毒品然后根据治疗目标的统计学比较评价BE标准 （超过治疗窗的患者比例和低于治疗窗的患者比例） 和仿制药此外，将评价PK生物等效性的不同标准，以确定 应选择哪种PK生物等效性标准以满足治疗生物等效性的给定标准 品牌和非品牌的区别该步骤将涉及模拟获批品牌和仿制药的PK和PD 被认为是NTI的药物。 从这项研究的成果将是一个）决策树，将结合定性和 用于决定药物是否属于NTI的定量特征B）NTI的生物等效性标准 包含已批准品牌和仿制药的PK和治疗窗信息的药物。

Project Summary The Code of Federal Regulations has defined narrow therapeutic index (NTI) drugs as those having less than 2 - fold difference in median lethal dose and median effective dose or have less than a 2 - fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood. However, there is lack of clear objective set of heuristics to define NTI. Having a clear objective definition is critical from regulatory and industry points of view. The CFR alludes to consider NTI as a factor during bioequivalence (BE) evaluation. There are several publications highlighting the negative impact on efficacy and safety if switching occurs between brand and generic forms of NTI drugs. Furthermore, the Advisory Committee for Pharmaceutical Sciences (ACPS) recommended in April 2010 meeting that the FDA should develop a list of NTI drugs with clear specialized criteria and the current BE standards are not sufficient for NTI drugs. This highlights the importance of development of precise, objective criteria for assessing the BE for NTI drugs. The objective of this research is to utilize principles of pharmacokinetics (PK), pharmacodynamics (PD) and steepness of PK/PD relationship to propose quantitative metrics to identify NTI drugs and propose BE criteria to better understand the difference between brand and generic drugs. Simulations as well as published literature information for NTI drugs will be utilized for analysis. Qualitative aspects including the severity of disease and reversibility of adverse events will be incorporated in the decision tree. The decision tree will be evaluated for sensitivity and specificity by applying to approved NTI and non NTI drugs. Followed by evaluation of BE criteria based on statistical comparison of therapeutic goalposts (proportion of patients exceeding and proportion of patients below the therapeutic window) for the brand and the generic drug. In addition, different criteria for PK bioequivalence will be evaluated to determine which PK bioequivalence criteria should be chosen to satisfy a given criteria for therapeutic bioequivalence between brand and generic. This step will involve simulations of PK and PD of approved brand and generic drugs considered as NTI. The deliverables from this research will be a) decision tree that will incorporate both qualitative and quantitative features for deciding whether a drug belongs to NTI or not b) bioequivalence criteria for NTI drugs incorporating information from PK and therapeutic window of approved brand and generic drugs.