Population Pharmacokinetic–B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Population Pharmacokinetic–B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis. / 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.
In: CNS Drugs, Vol. 36, No. 3, 2022, p. 283-300.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Population Pharmacokinetic–B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis
AU - Yu, Huixin
AU - Graham, Gordon
AU - David, Olivier J.
AU - Kahn, Joseph M.
AU - Savelieva, Marina
AU - Pigeolet, Etienne
AU - Das Gupta, Ayan
AU - Pingili, Ratnakar
AU - Willi, Roman
AU - Ramanathan, Krishnan
AU - Kieseier, Bernd C.
AU - Häring, Dieter A.
AU - Bagger, Morten
AU - Soelberg Sørensen, Per
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1007/s40263-021-00895-w
DO - 10.1007/s40263-021-00895-w
M3 - Journal article
C2 - 35233753
AN - SCOPUS:85125450713
VL - 36
SP - 283
EP - 300
JO - CNS Drugs
JF - CNS Drugs
SN - 1172-7047
IS - 3
ER -
ID: 314072724