Pan, S;
Yu, H;
Surti, A;
Cheng, I;
Marks, SD;
Brogan, PA;
Eleftheriou, D;
(2019)
Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.
British Journal of Clinical Pharmacology
, 85
(8)
pp. 1790-1797.
10.1111/bcp.13970.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bcp.13970 |
| Publisher version: | https://doi.org/10.1111/bcp.13970 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Autoimmune diseases, NONMEM, Paediatrics, Pharmacodynamics, Rituximab |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10073140 |
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