Population Pharmacokinetic–B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis
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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.
Original language | English |
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Journal | CNS Drugs |
Volume | 36 |
Issue number | 3 |
Pages (from-to) | 283-300 |
Number of pages | 18 |
ISSN | 1172-7047 |
DOIs | |
Publication status | Published - 2022 |
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