New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies

• Published in: Journal of neuroinflammation Vol. 13; no. 1; p. 164
• Main Authors: Sehr, T, Proschmann, U, Thomas, K, Marggraf, M, Straube, E, Reichmann, H, Chan, A, Ziemssen, T
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27-06-2016; BioMed Central
• Subjects: Adult; Antibodies - pharmacology; Antigens, CD; Disability Evaluation; Drug therapy; Female; Flow Cytometry; Follow-Up Studies; Health aspects; Humans; Immunologic Factors - blood; Immunologic Factors - cerebrospinal fluid; Immunologic Factors - therapeutic use; Integrin alpha4beta1 - metabolism; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - cerebrospinal fluid; Multiple Sclerosis - drug therapy; Natalizumab; Natalizumab - blood; Natalizumab - cerebrospinal fluid; Natalizumab - therapeutic use; Pharmacokinetics; Time Factors; Vascular Cell Adhesion Molecule-1 - metabolism; Switzerland; Germany; Treatment monitoring; Tysabri; Multiple sclerosis; Immunology; Natalizumab; CSF
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-016-0635-2

The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens.
We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy.
In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro.
Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.