Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2013- : Oxford : Wiley
      Original Publication: Stamford, Conn., Hall Associates.
    • Subject Terms:
      Models, Biological*; Multiple Sclerosis/*metabolism ; Natalizumab/*pharmacokinetics ; Natalizumab/*pharmacology; Adult ; Female ; Humans ; Integrin alpha Chains/immunology ; Male ; Middle Aged ; Multiple Sclerosis/blood ; Multiple Sclerosis/immunology ; Natalizumab/blood
    • Abstract:
      Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).
      (© 2017, The American College of Clinical Pharmacology.)
    • Contributed Indexing:
      Keywords: alpha-4 integrin; alpha-4 integrin saturation; multiple sclerosis; natalizumab; population pharmacokinetics
    • Accession Number:
      0 (Integrin alpha Chains)
      0 (Natalizumab)
    • Publication Date:
      Date Created: 20170412 Date Completed: 20180131 Latest Revision: 20220311
    • Publication Date:
      20231215
    • Accession Number:
      10.1002/jcph.894
    • Accession Number:
      28398628