Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases

摘要

Aims Rituximab 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. Methods Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2?×?750?mg/m 2 intravenous infusions of rituximab on days 1 and 15, or 4?×?375?mg/m 2 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. Results In 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/m 2 provides similar 6‐month suppression of CD19+ lymphocytes to current dosing. Conclusions Rituximab 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.