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

Sehr, T; Proschmann, U; Thomas, K; Marggraf, M; Straube, E; Reichmann, H; Chan, Andrew; Ziemssen, T (2016). New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies. Journal of neuroinflammation, 13(1), p. 164. BioMed Central 10.1186/s12974-016-0635-2

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BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology

UniBE Contributor:

Chan, Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1742-2094

Publisher:

BioMed Central

Language:

English

Submitter:

Stefanie Hetzenecker

Date Deposited:

12 Jul 2016 15:20

Last Modified:

12 Jul 2016 15:20

Publisher DOI:

10.1186/s12974-016-0635-2

PubMed ID:

27349895

Uncontrolled Keywords:

CSF; Immunology; Multiple sclerosis; Natalizumab; Treatment monitoring; Tysabri

BORIS DOI:

10.7892/boris.84404

URI:

https://boris.unibe.ch/id/eprint/84404

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