Rituximab
Rituximab induces a depletion of blood CD20+ B cells followed by reconstitution over subsequent
months and reduces the number of these cells in spleen and lymph nodes. In kidney transplantation, rituximab has been tested for reduction of blood group antibodies in blood group incompatible transplantation, in reducing the concentration of DSA in highly immunized recipients and to treat AMBR [30]. In an early trial using rituximab in renal transplant recipients the authors concluded that a single dose of rituximab, as opposed to repeated doses, was sufficient for sustained depression of B cells in peripheral blood. In that study all patients received 375mg/m2 [34]. In contrast to what was suggested by retrospective studies, later clinical trials using similar rituximab dose have not been able to confirm a significant benefit of rituximab on AMBR [30]. From the perspective of personalized dosing, it is of interest that in the study by Sautenet et al [35], 1-2 extra rescue administrations of rituximab was allowed. In the control group and in the rituximab group, this occurred for 42% and 32% of the patients respectively. Also, adverse reactions from rituximab are frequent, therefore one hypothesis would be that the introduction of MIPD might better predict the effective dose regimen already from the start –however this has not been addressed for transplanted populations.
Since rituximab has been used in several years for other diseases like rheumatoid arthritis, cancers and more, the PK/PD studies in these areas might indicate if and how personalized dosing could be introduced. A recent review on TDM of biologicals in rheumatoid arthritis [33] concluded that for rituximab the evidence was insufficient, but still that rituximab concentrations could predict the occurrence of ADAs and also in retrospect that lower rituximab levels preceded flares [36]. Studies in patients with lymphomas revealed log-fold inter-individual variability in rituximab concentrations indicating that median levels are not representative [37] and that time-changes in clearance could serve as a predictive marker of response [38]. This has also been suggested from recent trials of rituximab in multiple sclerosis [39]. Although different from the transplantation setting, these experiences with rituximab in divergent diseases, dosing regimens and drug combinations may be relevant for further trials were the potential benefit of MIPD could be explored.