Optimizing of Ciclosporin monitoring, towards improved ciclosporine therapy in children after stem cell transplantation

Ciclosporine a (CsA) is given to pediatric patients after their stem cell
transplantation (SCT) to prevent the occurrence of Graft-versus-Host Disease
(GVHD). Pharmacokinetic studies on CsA in different patient populations have
provided evidence that CsA dosing can be optimized when guided by determination
of CsA exposure (based on Area under the Curve (AUC) calculation). In the
pediatric population undergoing allogeneic SCT, CsA therapy monitoring is still
based in on trough levels. At this moment target AUC levels for CsA therapy in
these patients are not known and the relation with trough levels is unresolved.
In addition, the evidence for the currently applied target trough levels is
limited.
We hypothesize that CsA therapy to prevent GVHD can be optimized by AUC guided
dosing instead of dosing based on trough levels. Therefore, we will investigate
the association between CsA exposure and clinical outcome. Next to that, we
will investigate the association between CsA exposure and CsA trough levels.

To define the relation between CsA exposure and occurrence of acute
Graft-versus-Host disease. To investigate the relation between CsA exposure and
other clinical outcome parameters (engraftment, relapse, treatment related
toxicity and survival).
To investigate the association between CsA exposure and trough levels and
investigate the feasibility of CsA exposure monitoring using the limited
sampling model in clinical practice.

This is a multicenter prospective observational study.

In the pediatric population undergoing allogeneic stem cell transplantation CsA
therapy monitoring is still based in on trough levels. Earlier studies in solid
organ transplantation in both pediatric and adult patients demonstrated that
CsA dosing can be optimized when guided by CsA exposure. However, CsA exposure
is not studied before in this patient population in relation to clinical
outcome.
To minimize patient burden and study CsA exposure a limited sampling model was
developed, resulting in a reliable prediction of AUC using only 2 blood
samples. As these patients have a permanent venous access, we think the
addition of one blood samples per week (in hospital) and at another 2 time
points in the ambulant setting will not increase the burden of the patient
significantly.

This study will not be directly beneficial for the pediatric population
participating in the study. In the future, we will implement AUC guided
monitoring of CsA in normal patient care, provided that we can determine an
optimal AUC in relation to the occurrence of acute GVHD.