The pharmacokinetics and pharmacodynamics of eculizumab in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder
which is characterized by hemolytic anemia, cytopenias and thrombosis. PNH is
caused by clonal expansion of hematopoietic stem cells with an acquired somatic
mutation in the X-linked phosphatidylinositol glycan class A gene (4). This
gene encodes a protein required for synthesis of glycosylphosphatidylinositol
(GPI) anchors. As a result of the mutation, affected stem cells are deficient
in GPI anchored proteins. Clonal expansion leads to the production of
hematological cells lacking the expression of GPI anchored complement
regulatory proteins CD55 and CD59. This leads to chronic complement-mediated
hemolysis of the GPI-deficient erythrocytes. Eculizumab is a humanized chimeric
monoclonal anti-C5 inhibitor which is approved for the treatment of PNH and was
the first licensed drug targeting the complement system. By binding to C5,
eculizumab prevents the activation of C5 into C5a and C5b and subsequent the
formation of the terminal complement complex C5b-9. Eculizumab is currently
administered in a flat fixed dose for every patient. However, because of the
inter and intra individual variability in pharmacokinetics and pharmacodynamics
of eculizumab in PNH patients, a tailored treatment approach for the individual
is probably preferable. We have recently shown, by means of pharmacokinetic
modelling and simulation, based on the drug approval data, that eculizumab
dosing in PNH patients can be successfully tailored by means of Therapeutic
Drug Monitoring. This approach when implemented in practice will result in
overall less pharmacokinetic variability, less under-treatment and an average
dose reduction of 11%. It should be noted that the yearly eculizumab drug costs
are about 400.000 euro per patient. Considering the fact that in the
Netherlands alone approximately 60 patients with PNH are yearly treated with
this drug, this indicates that development of a model-informed precision dosing
tool based on the actual pharmacokinetics and pharmacodynamics of eculizumab
has the potential to decrease treatment costs with 2.640.000 euro on a yearly
basis.

The starting point of a robust tailored dosing approach for eculizumab is the
development of a population pharmacokinetic-pharmacodynamic model. The majority
of the pharmacokinetic and pharmacodynamic data in PNH patients are derived
from controlled clinical studies and may not be representative for general PNH
patient population. Therefore, it is pivotal to collect more pharmacokinetic
and pharmacodynamic data in PNH patients in the actual clinical setting.

To describe the real-world population pharmacokinetics and pharmacodynamics of
eculizumab in unselected PNH patients

This study is a cross-sectional observational pharmacokinetic and
pharmacodynamic study

The methods of this observational study are considered as minimally invasive
with negligible risks. The only risk associated with participation in this
study is collection of extra blood. We want to collect approximately 30 ml
blood in total, divided over 3 occasions per patient. After the infusion,
patients have to wait only 15 minutes before a blood sample can be collected.
Furthermore, patients can be benifit form this study, as we can probably
optimize their treatment with eculizumab.