Alemtuzumab
The approved indication for alemtuzumab is relapse-remitting multiple
sclerosis. Alemtuzumab is a humanized, monoclonal IgG1 antibody directed
against CD52 that is expressed on T and B
lymphocytes, as well as on natural killer (NK) cells and monocytes. In
renal transplantation the drug is used off-label both for induction and
as antirejection therapy. Although PK data exist from the use of this
drug in chronic lymphocytic leukemia (CLL), this is an example where
target-mediated clearance will differ between these two indications due
to the much higher load of CD52-positive cells in patients with CLL,
hence the extrapolation of PK data cannot be precisely extrapolated. The
PK of alemtuzumab has been investigated in renal transplant recipients
from a clinical trial where all patients received alemtuzumab sc
immediately before and 24hrs after transplantation for induction of
immunosuppression [40]. A large between-patient variability in
distribution and elimination was observed, and a PK model was developed
which showed an adequate concordance of the observed and population and
individual predicted alemtuzumab concentrations. The PK variability was
to a large degree explained by body size and the authors suggested that
lean BW-adjusted dosing can be applied to correct for this phenomenon,
showing potential as a marker to reduce between-subject variability in
alemtuzumab exposure.
Another recent study presented a model predicting the response to
alemtuzumab for acute kidney transplant rejection [41]. From the 115
patients a set of clinical and histological characteristics were
collected and logistic regression modelling was used to construct a
prognostic score enabling the accurate prediction of response which was
even further improved by including a set of targeted gene expressions.
This study did not include measurement of alemtuzumab concentrations.
Taking into account the efficient depletion of immune cells following an
alemtuzumab dose and the associated risk of infections, malignancy and
autoimmunity, and the fact that a single 30mg dose is used, it is
conceivable that many patients may be overdosed when treated for acute
rejection.
Taken together these recent studies suggest that follow-up studies on
the relation between alemtuzumab PK, lymphocyte dynamics and clinical
outcomes are warranted to further substantiate the clinical potential
and rationale for personalized alemtuzumab therapy in kidney
transplantation [40]. And as pointed out in an editorial [42]:
the combination of clinical and histologic data with molecular analysis
of renal allograft biopsies and pharmacokinetic data of the drug of
interest is the way forward.