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：肥胖引起的药物代动力学变化的机制 个体中药物的生物分散概况（药代动力学）受药物特性和受试者的控制 特征。肥胖引起的药物代动力学变化的基本机制尚未 经过足够的研究。除了肥胖，肥胖的特征是身体成分的改变（即 脂肪质量不正确的增加）。美国肥胖的患病率几乎翻了一番 1960年代初，全球超过16亿人被认为是肥胖或超重。鲜为人知 关于肥胖对各种药物类别生物分配的影响，而对最佳剂量尚无共识 已经建立了肥胖患者药物的策略。在靶标达到治疗药物浓度 成功的治疗结果需要部位。但是，我们在减肥手术的初步研究 患者在皮下脂肪组织中发现亚治性抗生素浓度在 关闭;其他研究人员也报告了类似的结果。这种药物暴露不足可能导致 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，肥胖患者的抗生素剂量策略目前是次优的，这可能导致 治疗失败。我们的数据还表明，抗体的药代动力学（免疫球蛋白G）也是 受肥胖的影响，这可能导致疗效降低和治疗毒性的增加。我们假设 肥胖症显着影响小分子药物和蛋白质疗法的生物脱位。更远， 结合身体成分和药代动力学建模的测量值可用于预测药物 肥胖患者的暴露并促进肥胖药物的药物选择和优化 人口。该提案的总体目标是确定肥胖如何影响β-的药代动力学 lactam抗生素和抗体，并开发数学模型，以预测在 肥胖患者。为了实现这一目标：1）研究肥胖症如何影响小型的药代动力学 使用头孢辛蛋白和哌啶/tazobactam组合的分子药物，肥胖的患者和 在肥胖的临床前模型中研究这些变化的机制； 2）调查肥胖 影响免疫球蛋白G（IgG）的药代动力学（许多蛋白质治疗和骨骼 肥胖人类患者的单克隆抗体），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是 伴随着人体组成的测量；和翻译数学模型将是 开发用于预测肥胖引起的这些药物和其他药物的药代动力学变化。 拟议的研究将填补关键的知识差距，以了解肥胖如何影响生物分裂 肥胖患者的药物以及如何进行药物选择和剂量优化。我们期待这一点 研究将对各种药物选择和给药实践具有重要的意义 药物并将提高肥胖人群的疗效和安全性。