Natalizumab Pharmacokinetics and -Dynamics and Serum Neurofilament in Patients With Multiple Sclerosis

Abstract

Background: Natalizumab (NAT) is a high-efficacy treatment for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy that sometimes requires treatment cessation with a risk of returning disease activity. The aim of this study was to characterize the pharmacokinetics and -dynamics as well as neurodestruction marker serum neurofilament light chain (sNfL) in patients with RRMS and secondary progressive MS (SPMS) stopping NAT in correlation to clinical data.Methods: In this study, 50 RRMS and 9 SPMS patients after NAT cessation were included. Five RRMS patients on NAT treatment holiday were evaluated. Clinical and radiological disease activity were systemically assessed by frequent exams after NAT stop. Free NAT concentration, cell bound NAT, α4-integrin expression and α4-integrin-receptor saturation as well as immune cell frequencies were measured for up to 4 months after NAT withdrawal. Additionally, sNfL levels were observed up to 12 months in RRMS and up to 4 months in SPMS patients.Results: NAT cessation was associated with a return of disease activity in 38% of the RRMS and 33% of the SPMS patients within 12 and 7 months, respectively. Concentration of free and cell bound NAT as well as α4-integrin-receptor saturation decreased in the RRMS and SPMS patients whereas α4-integrin expression increased over time. NAT induced increase of lymphocytes and its subsets normalized and a non-significant drop of NK and Th17 T-cells counts could be detected. All RRMS patients showed physiological sNfL levels <8pg/ml 1 month after last NAT infusion. During follow-up period sNfL levels peaked up to 16-fold and were linked to return of disease activity in 19 of the 37 RRMS patients. Treatment holiday was also associated with a return of disease activity in 4 of 5 patients and with an increase of sNfL at an individual level.Conclusions: We demonstrate the reversibility of NAT pharmacodynamic and -kinetic markers. sNfL levels are associated with the recurrence of disease activity and can also serve as an early marker to predict present before onset of clinical or radiological disease activity on the individual level.

Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation

“…Given the importance to maintaining an adequate treatment response during pregnancy in highly active MS, it is mandatory to understand whether pregnancy affects drug levels. For NAT, median serum trough concentration measured prior to pregnancy was similar to those levels reported in previous studies ( 26 , 34 – 37 ). Although pregnancy was associated with a non-significant drop of median NAT serum trough levels, median NAT trough concentration at the third trimester was still within the previous described range of pre-infusion NAT levels ( 26 , 34 – 36 ).…”

No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab

“… 8 In another study, sNfL remained stable for up to 8 weeks after discontinuing NZ, due to JC virus antibody positivity, but increased sNfL levels were detected at follow-up. 38 In a group of 60 stable MS patients on SID NZ treatment, no change in sNfL was seen at 6 months after switch to ⩾35 days dosing interval. 39 However, our study was the first to monitor sNfL at a relatively high frequency (every 6 weeks) for an extended period of time (48 weeks).…”

Long-term outcome of natalizumab-associated progressive multifocal leukoencephalopathy in Austria: a nationwide retrospective study

“…A narrowed T-cell repertoire and impaired T-cell functions in the aging immune system explain the rationale behind the immunosenescence theory, resulting in inappropriate cytotoxic T-cell activation that ultimately hampers viral clearance [ 38 – 40 ]. Therefore, once patients advance in treatment duration and age, the beneficial effect on disease control and the risk of rebound after stopping NAT [ 41 ] have to be weighed against increasing PML risk [ 42 ].…”