title: Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations.
abstract: BACKGROUND
  In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML.
  
  
  OBJECTIVE
  We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML.
  
  
  METHODS
  In a prospective observational cohort study of 219 patients with relapsing-remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12 weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups.
  
  
  RESULTS
  Mean natalizumab concentrations in the five patients developing PML was 18.9 µg/mL (standard deviation (SD): ±13.4) versus 23.8 µg/mL (SD: ±11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML.
  
  
  CONCLUSIONS
  Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PML.
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Zoé LE
authors.initials: ZL
authors.lastname: van Kempen
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Cyra E
authors.initials: CE
authors.lastname: Leurs
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: Vennegoor
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mike P
authors.initials: MP
authors.lastname: Wattjes
authors.affiliation: Landsteiner Laboratory, Department of Immunology, Sanquin Research, Amsterdam, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bernard Mj
authors.initials: BM
authors.lastname: Uitdehaag
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
mesh_terms: D000328:Adult; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D007968:Leukoencephalopathy, Progressive Multifocal / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000069442:Natalizumab / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D000069442:Natalizumab
keywords: Multiple sclerosis; extended dose interval; natalizumab; natalizumab concentration; progressive multifocal leukoencephalopathy