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.