TY - JOUR
T1 - Anti-rituximab antibodies affect pharmacokinetics and pharmacodynamics of rituximab in children with immune-mediated diseases
AU - Oomen, Ilja
AU - Rashid, Amara Nassar-Sheikh
AU - Bouts, Antonia H. M.
AU - Gouw, Samantha C.
AU - Kuijpers, Taco W.
AU - Rispens, Theo
AU - de Vries, Annick
AU - Wolbink, Gertjan
AU - van den Berg, J. Merlijn
AU - Schonenberg-Meinema, Dieneke
N1 - Funding Information: This work was supported by the Emma Children’s Hospital Foundation (in Dutch: Stichting Steun Emma). We would like to thank Paul Baars and Dr Ester van Leeuwen, both medical im munologists at the Amsterdam Univer sity Medical Center, for their assistance during this study. Publisher Copyright: © Clinical and Experimental Rheumatology 2022.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Objective Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR). Methods All children <18 years who had received RTX treatment in our center between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml. Results Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group. Conclusion In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.
AB - Objective Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR). Methods All children <18 years who had received RTX treatment in our center between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml. Results Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group. Conclusion In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.
KW - pharmacodynamics
KW - pharmacokinetics
KW - rituximab
UR - http://www.scopus.com/inward/record.url?scp=85127957573&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85127957573&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34251329
U2 - https://doi.org/10.55563/CLINEXPRHEUMATOL/FTIRA8
DO - https://doi.org/10.55563/CLINEXPRHEUMATOL/FTIRA8
M3 - Article
C2 - 34251329
SN - 0392-856X
VL - 39
SP - 183
EP - 190
JO - Clinical and experimental rheumatology
JF - Clinical and experimental rheumatology
IS - 5
ER -