那他珠单抗的临床药代动力学、药效学和药物基因组学综述：一种人源化抗α4 整合素单克隆抗体。

A Review on Clinical Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Natalizumab: A Humanized Anti-α4 Integrin Monoclonal Antibody.

机构信息

Department of Pharmacy, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.

出版信息

Curr Drug Metab. 2018;19(14):1213-1223. doi: 10.2174/1389200219666180427165841.

DOI:10.2174/1389200219666180427165841

PMID:29708072

Abstract

BACKGROUND

Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4β1 and α4β7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT.

METHODS

We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017).

RESULTS

Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS.

CONCLUSION

As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.

摘要

背景

那他珠单抗（NAT）是一种人源化单克隆抗体，可与 α4β1 和 α4β7 整合素结合，已被批准用于治疗多发性硬化症（MS）和克罗恩病（CD）。本综述重点介绍了 NAT 的详细药代动力学（PK）和药效动力学（PD）信息，以及 NAT 的药物基因组学（PG）特性。

方法

我们系统地检索了 Medline、EMBASE、Cochrane 图书馆电子数据库中的英文文献，以确定所有关于 NAT 的 PK、PD 或 PG 特性的潜在研究（截至 2017 年 10 月）。

结果

本综述纳入了 5 篇包含详细药代动力学参数的文献。体重是与 NAT 浓度最相关的重要因素。与肌内注射（IM）相比，皮下注射（SC）给药具有更好的 PK 相似性和 PD 可比性。在 SC 和静脉注射（IV）给药之间观察到初始 PK 差异。然而，在重复给药后，SC 和 IV 给药之间的 NAT 血清浓度相似。针对 NAT 的抗体导致血清 NAT 浓度降低，并导致 NAT 疗效丧失。NAT 结合的 α4 残基上的三个重要点突变是 Gln-152、Lys-201 和 Lys-256。Syndecan-1 基因是 NAT 在 MS 个体化应用的潜在候选基因。