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Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.
British Journal of Clinical Pharmacology 2019 April 27
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, United Kingdom. Dosing protocols were either two 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or four 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.
RESULTS: In total 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (%RSE) 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 a single infusion of 750 mg/m2 provides similar six-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.
METHODS: Routine electronic health record data were collected at a large paediatric tertiary hospital in London, United Kingdom. Dosing protocols were either two 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or four 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.
RESULTS: In total 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (%RSE) 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 a single infusion of 750 mg/m2 provides similar six-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.
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