A Review on Clinical Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Natalizumab: A Humanized Anti-

Abstract

Natalizumab (Tysabri®, Biogen-Idec Inc., NAT), a humanized anti-α4 integrin monoclonal antibody, binds in both α4β1 (Very Late Antigen 4, VLA-4) and α4β7 (lymphocytes Peyer's patch adhesion molecule 1, LPAM-1) integrins, is approved for the treatment of Multiple sclerosis (MS) and Crohn's disease (CD). NAT has been well tolerated in pivotal trials. Progressive multifocal leukoencephalopathy (PML) is an uncommon but serious complications resulting from NAT treatment. It is not confirmed that higher NAT concentration increases the risk of PML. NAT can pass placental barrier before delivery and into breast milk. As MS is a disease that affects young women most, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. Genome sequence variations in drug target proteins, drug-metabolizing enzymes, and drug transporters may alter the pharmacokinetics (PK) and pharmacodynamics (PD) properties of drugs and cause variable drug responses in individual patients. Pharmacogenomics research of NAT in MS or CD therapies are currently yielding an abundance of potential SNPs and markers of various outcomes of drug response. 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. However, the relationship between single nucleotide polymorphisms (SNPs) and NAT treatment are still not clear. Antibodies against NAT can also result in a low serum NAT concentration and causing a loss of efficacy of NAT. This review highlights the detailed PK and PD information of NAT, and PK and PD information in Asian population, with the pharmacogenomics properties of NAT.

Clinical adverse effects of natalizumab

“…[ 10 ] NAT is a nonselective anti-α 4 integrin monoclonal antibody, binding in both α 4 β 1 and α 4 β 7 integrins, could also be utilized in the treatment of CD. [ 11 ] CD is a relapsing inflammatory disease, which is a main component of inflammatory bowel disease, affecting the gastrointestinal tract. [ 12 ] NAT, opposing the α 4 chain of α 4 β 7 integrin and inhibiting the interaction of α 4 β 7 integrins with endothelial MAdCAM-1 (mucosal addressin cell adhesion molecule-1), leads to a interfere with the homing of lymphocytes to gastrointestinal lymphoid tissue.…”

“…[ 12 ] NAT, opposing the α 4 chain of α 4 β 7 integrin and inhibiting the interaction of α 4 β 7 integrins with endothelial MAdCAM-1 (mucosal addressin cell adhesion molecule-1), leads to a interfere with the homing of lymphocytes to gastrointestinal lymphoid tissue. [ 11 ]…”

Anti-integrins

“…The a4 integrin-dependent leukocyte trafficking promotes cognitive impairment in multiple sclerosis (MS), Alzheimer's disease (AD), and other neuropathological disorders, which suggests that blocking a4 integrins might offer a new therapeutic strategy in MS, AD, and other neuronal diseases. The FDA-approved humanized monoclonal antibody against the cell adhesion molecule a4integrin, namely natalizumab, is indicated for the improvement of disability and reduction of relapse rate in MS patients (Mazdeh et al 2018;Engelhardt and Kappos 2008;Li et al 2018;Manocha et al 2018;Dattoli et al 2018;Pietronigro et al 2019).…”

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children

“…Natalizumab was the first monoclonal antibody developed for treating MS and is still one of the most potent therapies for disease control. Natalizumab is a humanized monoclonal antibody that binds to integrins of both α4β1 (very late antigen 4, VLA-4) and α4β7 (lymphocyte Peyer’s patch adhesion molecule 1, LPAM-1) [153]. This unique mechanism of action blocks leukocyte attachment to cerebral endothelial cells, thus reducing inflammation at the blood–brain barrier and inside the central nervous system [154].…”

“…Breastfeeding is not recommended during natalizumab use, since the drug can be identified in breast milk [153, 167, 168]. Although the levels of natalizumab in breast milk are minute, breastfeeding safety cannot be determined at this time [168].…”