Abstract
AimsRituximab is a chimeric IgG‐1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell‐related pharmacodynamics of rituximab in children with autoimmune disease.MethodsRoutine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose–response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first‐order kinetics.ResultsIn total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days−1 and CD19+ turnover was 0.02 (41%) days−1 corresponding to half‐lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35‐fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6‐month suppression of CD19+ lymphocytes to current dosing.ConclusionsRituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.
Highlights
Rituximab is a chimeric murine/human monoclonal antibody that was first approved in 1997 by the US Food and Drug Administration for the treatment of non‐Hodgkin's lymphoma
The proposed K‐PD model with turnover mechanism gave a good description of the life span of CD19+ lymphocytes after rituximab treatment (Figures 2, 3), with CD19+ lymphocyte counts measured from children with multiple autoimmune diseases
We found that a single infusion of 750 mg/m2 or perhaps even 375 mg/m2 could be used for treating children with autoimmune diseases while retaining similar treatment effect as observed by CD19+ lymphocyte reduction within 6 months (Figure 4); the lowering rituximab dose would yield reduced treatment costs and possibly reduced infection risk
Summary
Rituximab is a chimeric murine/human monoclonal antibody that was first approved in 1997 by the US Food and Drug Administration for the treatment of non‐Hodgkin's lymphoma. Approval of rituximab was granted for the treatment of post‐transplant lymphoproliferative disorder and several autoimmune diseases including rheumatoid arthritis, granulomatosis with polyangiitis and other anti‐. Like most monoclonal antibodies, rituximab distributes and binds to FcRn receptors on the surface of endothelial cells to be protected from lysosomal degradation, which results in a long elimination half‐life.[4] Following rituximab treatment, the B‐lymphocyte depletion effect occurs rapidly, within 2 weeks, and persists for up to 6 months.[5,6]. The turnover half‐life of CD19+ lymphocytes and drug effect decay were similar in paediatric patients with autoimmune diseases than those observed in other populations. Current dosing schemes could be reduced by half and still give a similar degree of CD19+ suppression
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