DEVELOPMENTAL PHARMACOLOGY RESEARCH

研究人员指出，快速致命的感染和恶性肿瘤 艾滋病毒感染患者需要使用多种药物， 药物组合。 这些药物中有许多尚未得到充分评估， 在临床上发生的多种组合中，很少有评价 实践 本申请描述了一种基于数据的方法， 这些药物的临床药理学研究及其 组合。 一般做法是进行试点研究， 筛选药物相互作用或不良反应的预测因子。 临床 然后将使用专门设计的药物进行药理学研究， 在大量患者中使用。 具体目标如下：（1）检测和量化 用于治疗的药物之间的药代动力学和动态相互作用 HIV感染者。 (2)其次，申请人将评估 这些药物在特殊患者群体中的药代动力学， 包括少数民族，妇女，营养不良，酗酒， 静脉吸毒、艾滋病胃肠病和艾滋病心肌病。 （三） 接下来，申请人将尝试确定个体间 对治疗的反应和依从性的变化。 由于遗传 多态性是导致对大分子的不利或异常反应的原因。 药物数量，将要求在该ACTG研究中心入组的所有患者 志愿者用安全的原型药物进行简单的测试， 多态药物代谢的表型（例如，N-乙酰化，CYP 2D 6， CYP 3A 4，美芬妥英P450）。 对于在治疗期间不能免于药物治疗的患者， 基线检测时，将从0.5 ml 使用基于聚合酶链反应（PCR）的测定法对血液样本进行检测。 的 这些多态性中的每一种的预测能力将通过 将它们的通常分布与那些 药物不良反应（ADR）。 这些研究的结果， 申请人国家，应使个人的身份， 增加ADR或药物相互作用的风险。 此外，生物 将对这些因素进行分析，以检验它们可能影响 个体在决定接受研究性治疗时的行为，或 保持或遵守研究方案。 虽然要进行的确切研究只能在 ACTU协调委员会的咨询和审查，申请人 在此提出一项具体研究，以评估 膦甲酸（PFA），血清电解质变化和心脏电生理。 还有药物相互作用评价的一般方案 （具体目标#1）和特殊人群中的药代动力学（具体目标 #2）描述。 从这些研究中获得的信息应该允许 为艾滋病毒感染者提供治疗的医生 更好地了解其行动和不利影响的风险。

The investigators state that the rapid lethal infections and malignancies in patients with HIV infection prompts the use of many varied drugs and drug combinations. Many of these drugs have not been fully evaluated and few have been evaluated in the multiple combinations that occur in clinical practice. This application describes a data-based approach to the investigation of the clinical pharmacology of these drugs and their combinations. The general approach will be to conduct pilot studies to screen for drug interactions or predictors of adverse reactions. Clinical pharmacology studies will then be conducted using specifically designed protocols in larger numbers of patients. The specific aims are as follows: (1) The first is to detect and quantify pharmacokinetic and dynamic interactions between drugs used to treat patients with HIV infection. (2) Second, the applicants will evaluate the pharmacokinetics of these drugs in special populations of patients, including minorities, women, and those with malnutrition, alcoholism, intravenous drug use, AIDS gastroenteropathy and AIDS cardiomyopathy. (3) Next, the applicants will attempt to identify sources of inter-individual variation in response and adherence to therapy. Since genetic polymorphisms are responsible for adverse or aberrant responses to a large number of drugs, all patients enrolled at this ACTG site will be asked to volunteer for simple tests with safe prototypic drugs to identify their phenotype for polymorphic drug metabolism (e.g., N-acetylation, CYP2D6, CYP3A4, mephenytoin P450). For patients who cannot be drug free during baseline testing, their CYP2D6 genotype will be determined from a 0.5-ml blood sample using a polymerase chain reaction (PCR)-based assay. The predictive power of each of these polymorphisms will be examined by comparing their usual distributions to those in patients who develop adverse drug reactions (ADRs). The results of these studies, the applicants state, should make possible the identification of individuals at increased risk of ADRs or drug interactions. Additionally, the biological factors will be analyzed to test the hypothesis that they may influence the behavior of individuals in deciding to receive investigational therapy or to remain in, or comply with, a study protocol. Although the exact studies to be performed can only be determined after consultation and review by the ACTU coordinating committees, the applicants propose herein a specific study to evaluate the relationship between foscarnet (PFA), serum electrolyte changes and cardiac electrophysiology. Also general protocols for the evaluation of drug-drug interactions (specific aim #1) and pharmacokinetics in special populations (specific Aim #2) are described. The information from these studies should allow physicians caring for patients with HIV infection to provide therapy based on a greater understanding of its actions and risks for adverse effects.