PHARMACOKINETICS OF ANTITUBERCULOSIS DRUGS

抗结核药物的药代动力学

• 批准号: 2074722
• 负责人: Charles Arthur Peloquin
• 金额: $ 19.27万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2074722
• 关键词: adult human (21+); antacids; antitubercular agents; child (0-11); dosage; drug administration routes; drug screening /evaluation; fasting; human subject; newborn human (0-6 weeks); pharmacokinetics; tuberculosis

There are only nine FDA-approved drugs for the treatment of tuberculosis (TB). Most of the pharmacokinetic and pharmacodynamic data available for them are limited in scope, and were acquired with outdated techniques. Since there are no revolutionary antituberculosis drugs on the horizon, we must optimize our use of the available drugs. Mounting evidence points to definable relationships between the antituberculosis drug serum concentrations achieved in patients and their responses to treatment. If we are to improve the nearly 50% treatment failure rates for patients with multidrug-resistant tuberculosis (MDR-TB), it is critical that we define and exploit these relationships. Clearly defined therapeutic ranges for the antituberculosis drugs would allow clinicians to control and optimize the treatment of TB and especially MDR-TB. The overall goal of this study is to define the pharmacokinetic parameter values and key drug interactions for the antituberculosis drug. We will also determine how these values are altered by the host response to TB infection, concurrent illnesses, and extremes of age. This basic research will lead to maximum aposteriori probability (MAP) Bayesian and "multiple model" (MM) stochastic dosage design strategies for the individualization, adaptive control, and optimization of drug therapy for patients with TB and MDR-TB. It will also define relationships between the serum concentrations achieved and the clinical and bacteriological outcomes of treatment. We will research two specific areas. Project No. 1: We will perform randomized, cross-over pharmacokinetic studies in healthy volunteers. This will allow us to control a large number of variables that cannot be controlled in patients with TB. Subjects will receive (a) drugs taken in the fasted state, (b) drugs taken with food, and (c) drugs taken with antacids. Population pharmacokinetic models will be constructed for each antituberculosis drug using the USC*PACK software. We will determine six important endpoints: (1) true normal serum concentrations, (2) normal population pharmacokinetic parameter values, (3) the degree of intrasubject and intersubject variability in these values, and accurate recommendations regarding (4) which drugs must be taken on an empty stomach, (5) which drugs should be taken with food, and (6) which drugs must not be taken with antacids. Project No. 2: There are practically no data regarding the pharmacokinetics of the antituberculosis drugs in neonates and children, and the data for adults is sparse and does not address intermittent therapy. We will perform pharmacokinetic studies in neonates, children, and adults infected with TB and MDR-TB. Population pharmacokinetic mode's will be constructed as above. We will describe any changes in the parameter values caused by the host response to TB infection. We will seek to define unique subpopulations of TB patients based on age, selected concurrent illness, such as gastrointestinal, hepatic, or renal dysfunction, or AIDS. We will develop MAP Bayesian and MM stochastic dosage design strategies for the individualization and adaptive control of drug therapy for patients with TB and MDR-TB. We will also define relationships between the serum concentrations achieved and the clinical and bacteriological outcomes of treatment.

只有9种FDA批准的药物可以治疗结核病 （TB）。大多数药代动力学和药效数据可用于 它们的范围有限，并以过时的技术获取。 由于没有革命性的抗结核药物，我们 必须优化我们对可用药物的使用。安装证据指向 抗结核药物血清之间的可定义关系 患者达到的浓度及其对治疗的反应。如果 我们将针对患者提高近50％的治疗率 多药耐药性结核病（MDR-TB），我们定义至关重要 并利用这些关系。明确定义的治疗范围 抗结核药物将允许临床医生控制和优化 TB，尤其是MDR-TB的处理。 这项研究的总体目标是定义药代动力学参数 抗结核药物的值和关键药物相互作用。我们将 还确定主机对结核的响应如何改变这些值 感染，并发疾病和极端年龄。这项基础研究 将导致最大的aposteriori概率（MAP）贝叶斯和“多个 模型”（MM）个性化的随机剂量设计策略， 自适应控制和针对结核病患者的药物治疗优化 和MDR-TB。它还将定义血清之间的关系 达到的浓度以及临床和细菌结局 治疗。 我们将研究两个特定领域。项目1：我们将表演 健康志愿者中的随机，交叉药代动力学研究。这 将允许我们控制大量不能成为的变量 受结核病患者的控制。受试者将接受（a）吸毒 禁食状态，（b）用食物服用的药物，以及（c）服用的药物 抗酸剂。将为每个人建造种群药代动力学模型 使用USC*包装软件的抗结核药物。我们将确定六个 重要终点：（1）真正的正常血清浓度，（2）正常 人口药代动力学参数值，（3） 这些值中的受主体内和主体间的变异性，准确 关于（4）必须在空的中服用哪些药物的建议 胃，（5）应该用食物服用哪些药物，以及（6）哪些药物 不得与抗酸剂一起服用。 项目2：几乎没有关于 新生儿和儿童抗结核药物的药代动力学， 成人的数据很少，无法间歇 治疗。我们将在新生儿，儿童， 以及感染了TB和MDR-TB的成年人。人口药代动力学模式的模式 将如上所述构造。我们将描述 由主机对结核病感染的反应引起的参数值。我们将寻求 为了根据年龄定义结核病患者的独特亚群 并发疾病，例如胃肠道，肝或肾脏 功能障碍或艾滋病。我们将开发地图贝叶斯和MM随机 个性化和适应性控制的剂量设计策略 TB和MDR-TB患者的药物治疗。我们还将定义 达到的血清浓度与临床之间的关系 和治疗的细菌结局。