Mechanisms of obesity-induced changes in drug pharmacokinetics

肥胖引起的药物药代动力学变化的机制

• 批准号: 10373993
• 负责人: Leonid Kagan
• 金额: $ 46.28万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373993
• 关键词: Adipose tissue; Adolescent; Adult; Affect; Animal Model; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody-drug conjugates; Appendectomy; Biolectric Impedance; Body Composition; Body Size; Body Surface Area; Body Weight; Body measure procedure; Cefoxitin; Characteristics; Cholecystectomy; Clinical; Clinical Data; Clinical Research; Consensus; Cooperative Human Tissue Network; Data; Data Analyses; Dose; Drug Exposure; Drug Kinetics; Drug Modelings; Drug usage; Enrollment; Enzymes; Erythropoietin; Fatty acid glycerol esters; GTP-Binding Protein alpha Subunits, Gs; Goals; Health; Human; Immunoglobulin G; Individual; Investigation; Knowledge; Lead; Measurement; Measures; Modeling; Molecular; Monobactams; Monoclonal Antibodies; Obesity; Overweight; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Piperacillin-Tazobactam; Plasma; Population; Pre-Clinical Model; Prevalence; Property; Proteins; Public Health; Reporting; Research; Research Personnel; Risk; Safety; Sampling; Site; Skeleton; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Time; Tissues; Treatment Failure; Treatment-related toxicity; United States; Weight; X-Ray Computed Tomography; animal tissue; bariatric surgery; base; biological systems; drug modification; exenatide; human tissue; improved; individual patient; mathematical model; neonatal Fc receptor; obese patients; obese person; patient population; pharmacokinetic model; population based; pre-clinical; preclinical study; predictive modeling; repository; small molecule; subcutaneous; therapeutic protein; therapy outcome

Abstract Title: Mechanisms of obesity-induced changes in drug pharmacokinetics Biodisposition profile (pharmacokinetics) of a drug in an individual is governed by drug properties and subject characteristics. The underlying mechanisms of obesity-induced changes in drug pharmacokinetics have not been sufficiently studied. Beyond all, obesity is characterized by an alteration of body composition (i.e., disproportional increase in fat mass). The prevalence of obesity in the United States nearly doubled from the early 1960s, and over 1.6 billion people worldwide are considered obese or overweight. Little is known regarding the effects of obesity on biodisposition of various drug classes, and no consensus on the best dosing strategy for drugs in obese patients has been established. Attaining therapeutic drug concentration at target sites is required for successful therapeutic outcome. However, our preliminary study in bariatric surgery patients found subtherapeutic antibiotic concentration in the subcutaneous adipose tissue at the time of closure; and similar results were reported by other investigators. This inadequate drug exposure might result in therapy failure in a specific patient and lead to antibiotic resistance harming the population as a whole. Consequently, dosing strategies for antibiotics in obese patients are currently suboptimal, which might lead to treatment failure. Our data also indicate that pharmacokinetics of antibodies (Immunoglobulin G) is also affected by obesity, which may lead to decreased efficacy and increased toxicity of treatment. We hypothesize that obesity significantly affects the biodisposition of small-molecule drugs and protein therapeutics. Further, combining measurements of body composition and pharmacokinetic modeling can be used for predicting drug exposure in obese patients and facilitate drug selection and optimization of drug dosing in the obese population. The overall goal of this proposal is to determine how obesity affects pharmacokinetics of beta- lactam antibiotics and antibodies and to develop mathematical models for predicting drug biodisposition in obese patients. To achieve this we will: 1) Investigate how obesity affects the pharmacokinetics of small- molecule drugs using cefoxitin and piperacillin/tazobactam combination in obese human patients, and investigate the mechanisms of these changes in a preclinical model of obesity; 2) Investigate how obesity affects the pharmacokinetics of immunoglobulin G (IgG) (a protein therapeutic and skeleton for many monoclonal antibodies) in obese human patients, and investigate the mechanisms of obesity-induced changes in pharmacokinetics of IgG and other proteins in a preclinical model. Clinical and preclinical studies will be accompanied by measurement of the body composition; and translational mathematical models will be developed for predicting obesity-induced changes in pharmacokinetics of these and other drugs in humans. The proposed research will fill critical knowledge gaps in understanding how obesity affects the biodisposition of drugs and how drug selection and dose optimization can be achieved in obese patients. We anticipate this study will have a substantial and widespread significance on drug selection and dosing practices for various drugs and will improve efficacy and safety of therapy in obese population.

抽象的 标题：肥胖引起的药物药代动力学变化的机制 药物在个体中的生物处置特征（药代动力学）受药物特性和受试者的控制 特征。肥胖引起的药物药代动力学变化的潜在机制尚未阐明 得到了充分的研究。最重要的是，肥胖的特点是身体成分的改变（即， 脂肪量不成比例地增加）。美国的肥胖患病率比去年增加了近一倍 20 世纪 60 年代初，全世界有超过 16 亿人被认为肥胖或超重。鲜为人知 关于肥胖对各类药物生物处置的影响，并且对最佳剂量尚未达成共识 肥胖患者的药物策略已经制定。达到目标治疗药物浓度 成功的治疗结果需要位点。然而，我们在减肥手术方面的初步研究 患者在治疗时发现皮下脂肪组织中抗生素浓度低于治疗浓度 关闭;其他研究人员也报告了类似的结果。这种不充分的药物暴露可能会导致 特定患者的治疗失败并导致抗生素耐药性损害整个人群。 因此，目前肥胖患者的抗生素剂量策略并不理想，这可能会导致 治疗失败。我们的数据还表明，抗体（免疫球蛋白 G）的药代动力学也 受肥胖影响，可能导致治疗疗效下降和毒性增加。我们假设 肥胖显着影响小分子药物和蛋白质疗法的生物处置。更远， 结合身体成分测量和药代动力学模型可用于预测药物 肥胖患者的暴露并促进肥胖患者的药物选择和药物剂量优化 人口。该提案的总体目标是确定肥胖如何影响β- 内酰胺抗生素和抗体，并开发预测药物生物处置的数学模型 肥胖患者。为了实现这一目标，我们将： 1) 研究肥胖如何影响小剂量药物的药代动力学 使用头孢西丁和哌拉西林/他唑巴坦组合治疗肥胖人类患者的分子药物，以及 研究肥胖临床前模型中这些变化的机制； 2）调查肥胖如何发生 影响免疫球蛋白 G (IgG)（一种蛋白质治疗剂和许多药物的骨架）的药代动力学 单克隆抗体）在肥胖人类患者中，并研究肥胖引起的变化的机制 临床前模型中 IgG 和其他蛋白质的药代动力学。临床和临床前研究将 伴随身体成分的测量；平移数学模型将是 开发用于预测肥胖引起的这些药物和其他药物在人类中的药代动力学变化。 拟议的研究将填补了解肥胖如何影响生物处置的关键知识空白 药物的选择以及如何在肥胖患者中实现药物选择和剂量优化。我们预计这一点 研究将对各种疾病的药物选择和剂量实践具有重大和广泛的意义 药物，并将提高肥胖人群治疗的有效性和安全性。