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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Antidrug Antibodies Against Biological Treatments for Multiple Sclerosis

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  2. Targeting BKCa Channels in Migraine: Rationale and Perspectives

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Anti-CD20 Monoclonal Antibodies for Relapsing and Progressive Multiple Sclerosis

    Publikation: Bidrag til tidsskriftReviewForskningpeer review

  • Huixin Yu
  • Gordon Graham
  • Olivier J David
  • Joseph M Kahn
  • Marina Savelieva
  • Etienne Pigeolet
  • Ayan Das Gupta
  • Ratnakar Pingili
  • Roman Willi
  • Krishnan Ramanathan
  • Bernd C Kieseier
  • Dieter A Häring
  • Morten Bagger
  • Per Soelberg Sørensen
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BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses.

OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose.

METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses.

RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels.

CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.

OriginalsprogEngelsk
TidsskriftCNS Drugs
Vol/bind36
Udgave nummer3
Sider (fra-til)283-300
Antal sider18
ISSN1172-7047
DOI
StatusUdgivet - mar. 2022

Bibliografisk note

© 2022. The Author(s).

ID: 79739158