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.