健康韩国男性聚乙二醇化干扰素α-2a的群体PK-PD模型

StephenW

J Pharm Sci. 2018 Sep 1. pii: S0022-3549(18)30518-5. doi: 10.1016/j.xphs.2018.08.017. [Epub ahead of print]
Population PK-PD model of pegylated interferon alfa-2a in healthy Korean men.
Jung YS1, Chae D1, Park K2.
Author information

1
    Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
2
    Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].

Abstract

Pegylated interferon alfa-2a (PEG-IFN alfa-2a), which was developed to overcome the disadvantages of conventional formulations, is widely prescribed for hepatitis B or C virus infection. It is characterized by pharmacokinetic (PK) and pharmacodynamic (PD) properties much different from those of conventional forms. The present study developed a population PK-PD model of subcutaneous PEG-IFN α-2a in a Korean population. For PK, IFN alfa-2a concentrations were described by a one compartment model with first order absorption, preceded by skin-to-depot first order input. For PD, serum 2'-5' oligoadenylsynthetase (2'-5' OAS) activity was described by an effect compartment model incorporating a tolerance compartment. The baseline serum 2'-5' OAS level was found to have an inverse relationship with sensitivity to tolerance, leading to high tolerance at low baseline. The model revealed that subjects with low baselines experienced time delay, while those with high baselines showed tolerance in their concentration-effect relationships. The developed models matched well with data and simulation results, and the model showed that the optimal dose decreases with the baseline, with no dose effective for a baseline > 250pmol/dl. Our results can serve as a basis for improving dosing regimens of PEG-IFN α-2a in adult patients with chronic hepatitis B or C infection.
KEYWORDS:

2’-5’ OAS; Allometry; Interferon; NONMEM; Pegylation; Population PK-PD; Tolerance

PMID:
    30179597
DOI:
    10.1016/j.xphs.2018.08.017

StephenW

J Pharm Sci。 2018年9月1日.pii：S0022-3549（18）30518-5。 doi：10.1016 / j.xphs.2018.08.017。 [提前打印]
健康韩国男性聚乙二醇化干扰素α-2a的群体PK-PD模型。
Jung YS1，Chae D1，Park K2。
作者信息

1
    韩国延世大学医学院药理学系，韩国首尔;脑韩国21 Plus医学科学项目，韩国首尔延世大学。
2
    韩国延世大学医学院药理学系。电子地址：[email protected]。

抽象

聚乙二醇化干扰素α-2a（PEG-IFNα-2a）是为克服常规制剂的缺点而开发的，广泛用于乙型肝炎或丙型肝炎病毒感染。其特征在于药代动力学（PK）和药效学（PD）性质与常规形式的性质大不相同。本研究在韩国人群中开发了皮下PEG-IFNα-2a的群体PK-PD模型。对于PK，IFNα-2a浓度通过具有一级吸收的一室模型描述，之前是皮肤 - 贮库一级输入。对于PD，通过包含耐受室的效应室模型描述了血清2'-5'寡聚腺苷酸合成酶（2'-5'OAS）活性。发现基线血清2'-5'OAS水平与对耐受性的敏感性成反比关系，导致低基线时的高耐受性。该模型显示，基线较低的受试者经历了时间延迟，而具有高基线的受试者表现出其浓度 - 效应关系的耐受性。所开发的模型与数据和模拟结果匹配良好，并且模型显示最佳剂量随基线降低，对于基线> 250pmol / dl没有剂量有效。我们的结果可作为改善成人慢性乙型肝炎或丙型肝炎感染患者PEG-IFNα-2a给药方案的基础。
关键词：

2'-5'AS;异速生长;干扰素; NONMEM;聚乙二醇化;人口PK-PD;公差

结论：
    30179597
DOI：
    10.1016 / j.xphs.2018.08.017