Trond Trætteberg Serkland, Anna-Kristina Fredheim Oma, Erik I Hallin, Mathias H Øverås, Gro Owren Nygaard, Kjell-Morten Myhr, Øivind Torkildsen, Susanna Röblitz, Silje Skrede
A novel PKPD model for OCR in RRMS that integrates drug exposure and CD19⁺ lymphocyte kinetics is presented. Although a small number of patients is included in the current study, this framework represents an important step toward clinically applicable, model-informed dosing strategies, with the potential to enhance treatment precision and support personalized therapy in RRMS.
BACKGROUND AND OBJECTIVE: Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although the standard regimen consists of fixed 6-monthly infusions, therapeutic duration may vary between patients, highlighting the need for individualized dosing strategies. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model able to predict patient-specific treatment responses, as a step towards a clinically applicable tool for optimizing OCR dosing precision in RRMS.
METHODS: Serum OCR concentrations and CD19⁺ lymphocyte counts from 11 treatment-naïve patients with newly diagnosed RRMS were analyzed. Samples were collected over 24 weeks following the first and second OCR infusions. Data were analyzed using a nonlinear mixed-effects population modelling approach in Monolix Suite 2023R1, with parameter estimation performed via the stochastic approximation expectation-maximization algorithm. Several structural models were evaluated, and model performance was assessed by fit statistics and visual predictive checks.
RESULTS: The resultant two-compartment PKPD model successfully described OCR disposition and CD19⁺ lymphocyte depletion/repopulation. The final model included clearance of OCR without target-mediated elimination and described the effect of OCR on the dynamics of CD19⁺ lymphocyte counts. Simulations demonstrated the ability of the model to estimate the time to CD19⁺ lymphocyte repopulation and to explore optimal time for follow-up measurements.
CONCLUSION: A novel PKPD model for OCR in RRMS that integrates drug exposure and CD19⁺ lymphocyte kinetics is presented. Although a small number of patients is included in the current study, this framework represents an important step toward clinically applicable, model-informed dosing strategies, with the potential to enhance treatment precision and support personalized therapy in RRMS.
CLINICAL TRIALS REGISTRATION NUMBER: OVERLORD-MS: NCT04578639, ROS-MS: NCT06663111.