Suppr超能文献

纳入皮下注射聚乙二醇化肽淋巴吸收的基于人群生理学的药代动力学模型。

Population physiologically-based pharmacokinetic model incorporating lymphatic uptake for a subcutaneously administered pegylated peptide.

作者信息

Offman Elliot, Phipps Colin, Edginton Andrea N

机构信息

School of Pharmacy, University of Waterloo, 200 University Ave W, Waterloo, ON, N2L 3G1, Canada.

出版信息

In Silico Pharmacol. 2016 Dec;4(1):3. doi: 10.1186/s40203-016-0018-5. Epub 2016 Mar 1.

Abstract

PURPOSE

Physiologically-based pharmacokinetic (PBPK) models provide a rational mechanistic approach for predicting the time course of macromolecules in plasma. Population PBPK models for large molecules necessitate incorporation of lymphatic circulation to mechanistically account for biodistribution. Moreover, characterization of subcutaneous absorption requires consideration of the microvascular transit from the injection site to the systemic circulation. A PBPK model for a pegylated peptide conjugate, previously developed for primates, was modified to describe the lymphatic uptake in a population of humans by incorporation of interindividual variability in the lymphatic circulation and a unique lymphatic drainage compartment (LDC). The model was then used to simulate the time course of the drug in a population of humans and compared to the same drug administered to a group of human subjects participating in a first-in-human study.

METHODS

Organ, blood and lymph masses for the population were sampled from either normal or log-normal distributions. Blood flows were calculated for each organ based on mean organ perfusion per gram of organ tissue and lymphatic flow was set as a fixed fraction of blood flow. Interindividual variability in lymphatic volume was assumed to be similar to that of blood volume. The volume of the LDC was parameterzed as a fraction of the injection volume. Sensitivity analysis was performed to study uncertain parameters and distribution assumptions.

RESULTS

The population generator was capable of simulating a virtual population incorporating the lymphatic circulation. Incorporation of a LDC resulted in similar line shape relative to the observed data and incorporation of anthropometric variability accounted for individual differences in the absorption and elimination phases across all dose cohorts. Line shape was sensitive to the inclusion of LDC while peak and elimination portions of the time course were influenced by the magnitude of variance assumed for blood volume and renal clearance, respectively.

CONCLUSION

Lymphatic circulation can be incorporated into a population PBPK model assuming similar interindividual variability as observed for blood volume. Incorporation of an LDC, where the volume of this transit compartment is proportional to the SC injection volume may be an important mechanistic means of predicting the transit from the SC depot to the systemic circulation.

摘要

目的

基于生理学的药代动力学(PBPK)模型为预测血浆中大分子的时程提供了一种合理的机制方法。针对大分子的群体PBPK模型需要纳入淋巴循环,以便从机制上解释生物分布。此外,皮下吸收的特征描述需要考虑从注射部位到体循环的微血管转运。先前为灵长类动物开发的聚乙二醇化肽缀合物的PBPK模型,通过纳入淋巴循环中的个体间变异性和一个独特的淋巴引流隔室(LDC)进行了修改,以描述人类群体中的淋巴摄取。然后使用该模型模拟药物在人类群体中的时程,并与给予一组参与首次人体研究的人类受试者的相同药物进行比较。

方法

群体的器官、血液和淋巴质量从正态分布或对数正态分布中采样。根据每克器官组织的平均器官灌注计算每个器官的血流量,并将淋巴流量设定为血流量的固定比例。假定淋巴体积的个体间变异性与血容量的变异性相似。LDC的体积参数化为注射体积的一部分。进行敏感性分析以研究不确定参数和分布假设。

结果

群体生成器能够模拟纳入淋巴循环的虚拟群体。纳入LDC导致与观察数据相比具有相似的线形,并且纳入人体测量学变异性解释了所有剂量队列中吸收和消除阶段的个体差异。线形对LDC的纳入敏感,而时程的峰值和消除部分分别受血容量和肾清除率假定方差大小的影响。

结论

假设与血容量观察到的个体间变异性相似,可以将淋巴循环纳入群体PBPK模型。纳入一个LDC,其中这个转运隔室的体积与皮下注射体积成比例,可能是预测从皮下 depot到体循环转运的重要机制手段。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a43/4773320/308d2f8d41dd/40203_2016_18_Fig1_HTML.jpg

相似文献

2
A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide.
J Pharmacokinet Pharmacodyn. 2015 Apr;42(2):135-50. doi: 10.1007/s10928-015-9406-4. Epub 2015 Feb 4.
8
Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.
Drug Metab Dispos. 2012 May;40(5):952-62. doi: 10.1124/dmd.111.043604. Epub 2012 Feb 10.
10
Lymphatic absorption, metabolism, and excretion of a therapeutic peptide in dogs and rats.
Drug Metab Dispos. 2013 Dec;41(12):2206-14. doi: 10.1124/dmd.113.051524. Epub 2013 Oct 2.

引用本文的文献

4
Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics.
Drug Metab Dispos. 2022 Jun;50(6):867-878. doi: 10.1124/dmd.121.000460. Epub 2022 Feb 23.
6
A PBPK model describing the pharmacokinetics of γ-HBCD exposure in mice.
Toxicol Appl Pharmacol. 2021 Oct 1;428:115678. doi: 10.1016/j.taap.2021.115678. Epub 2021 Aug 11.
7
Current and prospective computational approaches and challenges for developing COVID-19 vaccines.
Adv Drug Deliv Rev. 2021 May;172:249-274. doi: 10.1016/j.addr.2021.02.004. Epub 2021 Feb 6.
8
Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling.
J Pharmacokinet Pharmacodyn. 2020 Oct;47(5):385-409. doi: 10.1007/s10928-020-09691-3. Epub 2020 Jun 4.
9
A modeling platform for the lymphatic system.
J Theor Biol. 2020 May 21;493:110193. doi: 10.1016/j.jtbi.2020.110193. Epub 2020 Feb 28.

本文引用的文献

2
A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant.
Regul Toxicol Pharmacol. 2015 Apr;71(3):353-64. doi: 10.1016/j.yrtph.2015.02.005. Epub 2015 Feb 12.
3
A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide.
J Pharmacokinet Pharmacodyn. 2015 Apr;42(2):135-50. doi: 10.1007/s10928-015-9406-4. Epub 2015 Feb 4.
4
Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis?
Drug Discov Today. 2014 Oct;19(10):1623-31. doi: 10.1016/j.drudis.2014.06.002. Epub 2014 Jun 11.
5
A physiologically-based pharmacokinetic (PBPK) model of squalene-containing adjuvant in human vaccines.
J Pharmacokinet Pharmacodyn. 2013 Oct;40(5):545-56. doi: 10.1007/s10928-013-9328-y. Epub 2013 Aug 4.
6
PopGen: A virtual human population generator.
Toxicology. 2014 Jan 6;315:70-85. doi: 10.1016/j.tox.2013.07.009. Epub 2013 Jul 19.
7
Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.
AAPS J. 2013 Apr;15(2):377-87. doi: 10.1208/s12248-012-9446-2. Epub 2012 Dec 27.
9
An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry.
Crit Rev Toxicol. 2012 Oct;42(9):751-67. doi: 10.3109/10408444.2012.709225. Epub 2012 Sep 7.
10
Normal reference values for glomerular filtration rate: what do we really know?
Nephrol Dial Transplant. 2012 Jul;27(7):2664-72. doi: 10.1093/ndt/gfs265.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验