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

Abstract

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.

Fig. 1

Modeling steps and results. LLN lower limit of normal, PK pharmacokinetics, q4w every 4 weeks, RMS relapsing multiple sclerosis, TMDD target-mediated drug disposition

Fig. 2

Cumulative volume of new Gd+ T1 lesions at week 24 by CD19+ B cell count and the number of Gd+ T1 lesions at screening. Gd+ gadolinium-enhancing, SE standard error

Fig. 3

Schematic structure of the final model. EC₅₀ concentration producing 50% of maximum drug effect, E_max maximum drug effect, k_deg receptor degradation rate constant, k_e(L) elimination rate constant for ligand, k_e(P) elimination rate constant for complex, k_in B cell input rate, k_off dissociation rate constant, k_on binding rate, k_out B cell elimination rate constant, k_syn synthesis rate constant, L ligand, Q intercompartmental flow, QB flow between B cell compartments, V_b peripheral volume of distribution of B cells, V_c central volume of distribution, V_p peripheral volume of distribution of ofatumumab

Fig. 4

Relationship between ofatumumab doses and B cell depletion at 7 days, 28 days, 3 months, 6 months, 1 year, and 2 years. Box and whisker plots of simulated B cell counts (middle line = median; box = 25th and 75th quartiles [IQR]; lower/upper lines = 1.5 × IQR; points = outliers); simulations performed for the various dosage regimens administered SC with the prefilled syringe with the standard phase 3 schedule (i.e., three loading doses given weekly followed by monthly doses) and for the patient population included in the five studies. The dashed line indicates the B cell counts at lower limit of normal level (40 cells/µL); the dash-dotted line indicates the B cell target (8 cells/µL). IRQ interquartile range, SC subcutaneously

Fig. 5

Simulated ofatumumab plasma concentration–time profiles. Over 1 year (Left panel); after last dose at 2 years (Right panel). Simulated median and 90% prediction interval; simulations performed for the phase 3 dosage regimen administered SC with the prefilled syringe (i.e., three loading 20-mg doses given weekly followed by monthly 20-mg doses) and for the patient population included in the five studies

Fig. 6

Simulated B cell count. B cell depletion over the first 24 weeks of treatment (Left panel); B cell repletion after treatment stops after 2 years (Right panel). Simulated median B cell count and 90% prediction interval; simulations performed for the phase 3 dosage regimen administered SC with the prefilled syringe (i.e., three loading 20-mg doses given weekly followed by monthly 20-mg doses) and for the patient population included in the five studies. The dashed line indicates the B cell counts at lower limit of normal level (40 cells/µL); the dash-dotted line indicates the B cell target (8 cells/µL). SC subcutaneously

Fig. 7

Simulated steady state AUC week 104 to week 108 by weight. Box and whisker plots of AUCs calculated from individual patient simulated PK profiles (middle line = median; box = 25th and 75th quartiles [IQR]; lower/upper lines = 1.5 × IQR; points = outliers); PK profiles are for subcutaneous route with prefilled syringe and using phase 3 dosage regimen (i.e., three loading 20-mg doses given weekly followed by monthly 20-mg doses). AUC area under the curve, IRQ interquartile range, PK pharmacokinetic

Fig. 8

Proportion of CD19+ B cell depletion over time by patient weight quartile. Simulation is for subcutaneous route with prefilled syringe and using phase 3 dosage regimen (i.e., three loading 20-mg doses given weekly followed by monthly 20-mg doses)