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

• Published in: CNS drugs Vol. 36; no. 3; pp. 283 - 300
• Main Authors: Yu, Huixin, Graham, Gordon, David, Olivier J., Kahn, Joseph M., Savelieva, Marina, Pigeolet, Etienne, Das Gupta, Ayan, Pingili, Ratnakar, Willi, Roman, Ramanathan, Krishnan, Kieseier, Bernd C., Häring, Dieter A., Bagger, Morten, Soelberg Sørensen, Per
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-03-2022; Springer Nature B.V
• Subjects: Adult; Adults; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - therapeutic use; Antigens; B-Lymphocytes; Body weight; CD20 antigen; Cytotoxicity; Disease; Epitopes; Humans; Medicine; Medicine & Public Health; Monoclonal antibodies; Multiple sclerosis; Multiple Sclerosis - drug therapy; Nervous system; Neurology; Neurosciences; Original; Original Research Article; Patients; Pharmacokinetics; Pharmacotherapy; Population; Psychiatry; Psychopharmacology; Recurrence; Regression analysis; United States > US
• ISSN: 1172-7047; 1179-1934
• DOI: 10.1007/s40263-021-00895-w

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.