肥胖诱导大鼠 IgG 药代动力学变化的机制。

Mechanisms of Obesity-Induced Changes in Pharmacokinetics of IgG in Rats.

机构信息

Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.

Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.

出版信息

Pharm Res. 2023 May;40(5):1223-1238. doi: 10.1007/s11095-023-03496-y. Epub 2023 Mar 22.

DOI:10.1007/s11095-023-03496-y

PMID:36949370

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10033182/

Abstract

PURPOSE

To evaluate how obesity affects the pharmacokinetics of human IgG following subcutaneous (SC) and intravenous (IV) administration to rats and the homeostasis of endogenous rat IgG.

METHODS

Differences in body weight and size, body composition, and serum concentration of endogenous rat IgG in male Zucker obese (ZUC-FA/FA) and control (ZUC-LEAN) rats were measured from the age of 5 weeks up to 30 weeks. At the age of 23-24 weeks animals received a single IV or SC dose of human IgG (1 g/kg of total body weight), and serum pharmacokinetics was followed for 7 weeks. A mechanistic model linking obesity-related changes in pharmacokinetics with animal growth and changes in body composition was developed.

RESULTS

Significant differences were observed in both endogenous and exogenous IgG pharmacokinetics between obese and control groups. The AUC for human IgG was lower in obese groups (57.6% of control after IV and 48.1% after SC dosing), and clearance was 1.75-fold higher in obese animals. The mechanistic population model successfully captured the data and included several major components: endogenous rat IgG homeostasis with age-dependent synthesis rate; competition of human IgG and endogenous rat IgG for FcRn binding and its effect on endogenous rat IgG concentrations following injection of a high dose of human IgG; and the effect of body size and composition (changing over time and dependent on the obesity status) on pharmacokinetic parameters.

CONCLUSIONS

We identified important obesity-induced changes in the pharmacokinetics of IgG. Results can potentially facilitate optimization of the dosing of IgG-based therapeutics in the obese population.

摘要

目的

评估肥胖如何影响皮下（SC）和静脉内（IV）给予大鼠后人 IgG 的药代动力学以及内源性大鼠 IgG 的体内平衡。

方法

从 5 周龄到 30 周龄，测量雄性 Zucker 肥胖（ZUC-FA/FA）和对照（ZUC-LEAN）大鼠的体重和体型差异、身体成分以及内源性大鼠 IgG 的血清浓度。在 23-24 周龄时，动物接受单次 IV 或 SC 剂量的人 IgG（1 g/kg 体重），并在接下来的 7 周内监测血清药代动力学。建立了一个将肥胖相关的药代动力学变化与动物生长和身体成分变化联系起来的机制模型。

结果

肥胖组和对照组之间均观察到内源性和外源性 IgG 药代动力学的显著差异。肥胖组的人 IgG AUC 较低（IV 后为对照组的 57.6%，SC 后为 48.1%），清除率高出 1.75 倍。该机制群体模型成功地捕获了数据，并包含了几个主要组成部分：随年龄变化的内源性大鼠 IgG 内稳态，具有依赖性合成率；人 IgG 和内源性大鼠 IgG 对 FcRn 结合的竞争及其对注射高剂量人 IgG 后内源性大鼠 IgG 浓度的影响；以及体型和组成（随时间变化并依赖于肥胖状态）对药代动力学参数的影响。