Mechanisms of obesity-induced changes in drug pharmacokinetics

摘要 肥胖引起药物药代动力学变化的机制 药物在个人体内的生物处置情况(药代动力学)受药物特性和受试者的支配 特点。肥胖引起的药物药代动力学变化的潜在机制还没有 已经得到了充分的研究。最重要的是，肥胖的特征是身体成分的改变(即， 脂肪质量不成比例的增加)。美国的肥胖率几乎比去年翻了一番 20世纪60年代初，全球有超过16亿人被认为肥胖或超重。鲜为人知 关于肥胖对不同药物类别生物处置的影响，对最佳剂量没有达成共识 肥胖患者的用药策略已经制定。达到靶向治疗药物浓度 要取得成功的治疗结果，就需要有合适的部位。然而，我们在减肥外科的初步研究 患者在皮下脂肪组织中发现了低于治疗性的抗生素浓度 其他调查人员也报告了类似的结果。这种不充分的药物暴露可能导致 治疗在特定患者中失败，并导致抗生素耐药性损害整个人群。 因此，肥胖症患者的抗生素剂量策略目前并不理想，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，可能导致治疗效果下降和毒性增加。我们假设 肥胖显著影响小分子药物和蛋白质疗法的生物处置。此外， 结合人体成分测量和药代动力学模型可用于药物预测 肥胖患者的暴露和促进肥胖者的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-氨基丁酸的药代动力学。 内酰胺类抗生素和抗体，并建立预测药物生物处置的数学模型。 肥胖的病人。为了实现这一目标，我们将：1)调查肥胖如何影响小鼠的药代动力学。 头孢西丁和哌拉西林/他唑巴坦联合应用于肥胖患者的分子药物，以及 在肥胖的临床前模型中研究这些变化的机制；2)研究肥胖是如何 影响免疫球蛋白G(Ig G)(一种治疗多种疾病的蛋白质和骨骼)的药代动力学 单抗)，并探讨肥胖引起的改变的机制 在临床前模型中研究免疫球蛋白和其他蛋白质的药代动力学。临床和临床前研究将 伴随着身体成分的测量；转换的数学模型将被 开发用于预测肥胖引起的这些药物和其他药物在人类体内的药代动力学变化。 这项拟议的研究将填补在理解肥胖如何影响生物倾向方面的关键知识空白。 以及如何在肥胖患者中实现药物选择和剂量优化。我们预料到了这一点 这项研究将对各种药物的选择和给药实践具有重大而广泛的意义 并将提高肥胖人群治疗的有效性和安全性。

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.