Mechanisms of obesity-induced changes in drug pharmacokinetics

摘要 标题：肥胖诱导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）受药物性质和受试者的控制 特色肥胖引起的药物药代动力学变化的潜在机制尚未得到证实。 已被充分研究。除此之外，肥胖的特征是身体组成的改变（即， 脂肪量不成比例地增加）。美国的肥胖率几乎是2010年的两倍。 自20世纪60年代初以来，全球有超过16亿人被认为肥胖或超重。知之甚少 关于肥胖对各种药物生物处置的影响，以及对最佳剂量没有达成共识 肥胖患者的药物治疗策略已经确立。达到目标治疗药物浓度 成功的治疗结果需要的部位。然而，我们对减肥手术的初步研究 患者在皮下脂肪组织中发现亚治疗抗生素浓度， 关闭;其他研究者报告了类似的结果。这种药物暴露不足可能导致 在特定患者中治疗失败并导致抗生素耐药性危害整个人群。 因此，肥胖患者的抗生素给药策略目前是次优的，这可能导致 治疗失败。我们的数据还表明，抗体（免疫球蛋白G）的药代动力学也是 受肥胖影响，这可能导致疗效降低和治疗毒性增加。我们假设 肥胖显著影响小分子药物和蛋白质治疗剂的生物处置。此外，本发明还 结合身体组成的测量和药代动力学建模可用于预测药物代谢。 并促进肥胖患者中药物选择和药物剂量的优化 人口这项提案的总体目标是确定肥胖如何影响β- 内酰胺类抗生素和抗体，并开发数学模型，用于预测药物的生物处置， 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分子药物的药代动力学， 在肥胖人类患者中使用头孢西丁和哌拉西林/他唑巴坦组合的分子药物，以及 在肥胖的临床前模型中研究这些变化的机制; 2）研究肥胖如何 影响免疫球蛋白G（IgG）（一种蛋白质治疗剂和许多人的骨架）的药代动力学 单克隆抗体），并研究肥胖诱导的变化的机制 IgG和其他蛋白质在临床前模型中的药代动力学。临床和临床前研究将 伴随着身体成分的测量;和翻译的数学模型将 开发用于预测肥胖诱导的这些和其他药物在人体内的药代动力学变化。 这项拟议中的研究将填补关键的知识空白，以了解肥胖如何影响生物处置。 以及如何在肥胖患者中实现药物选择和剂量优化。我们预料到这一点 研究将对各种疾病的药物选择和给药实践具有实质性和广泛的意义。 药物，并将提高治疗肥胖人群的疗效和安全性。

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.