A Multi Center, Prospective, Observational, Open-label, Pharmacokinetic Study of Tacrolimus in Heart and Lung Transplantation Patients during the First Days after Transplantation

Tacrolimus is an immunosuppressive agent used as prophylaxis for organ
rejection in lung, heart, liver and kidney transplantation. In previous
studies, high inter- and intra-individual variability in tacrolimus blood
concentration has been observed among transplant recipients. The range and the
factors explaining variation in tacrolimus blood concentrations during the
first days post-transplantation in heart and lung transplant recipients are
largely unknown. More insight on factors causing the inter- and
intra-individual variability in tacrolimus concentrations is necessary in order
to adapt dose regimen to individuals. Individualization of dosing regimen is
needed to prevent organ toxicity, if tacrolimus concentration is too high, and
organ rejection, if tacrolimus concentration is too low or in other words, to
improve safety of tacrolimus and minimize toxicity directly after heart and
lung transplantation.

Primary objective:
To show that the variability of whole blood total and unbound plasma tacrolimus
concentrations during the first 6 days post transplantation is larger than the
variation of tacrolimus concentrations in stable clinical situation.

Secondary objectives:
* To show that unbound tacrolimus plasma concentrations can better predict the
occurrence of renal dysfunction than whole blood total tacrolimus
concentrations.
* Identification of variables influencing the unbound tacrolimus plasma
concentrations.
* To evaluate whether variations in tacrolimus concentrations in the first days
after lung transplantation in cystic fibrosis patients are higher than without
cystic fibrosis.


Long-term objective:
* The data will be used to develop a kinetic model in the future in order to
dose tacrolimus more accurately to prevent adverse effects of tacrolimus.

We will perform a multiple doses, open-label, observational, prospective and
single-center study in heart and lung transplant recipients. Pharmacokinetic
parameters will be observed in 30 heart and lung transplant recipients up to
the first 6 days after transplantation or shorter if patients are discharged
from the intensive care earlier. Renal function will be evaluated in the first
days and circa 1, 3 and 6 months after transplantation in the out-patient
department.

Risk: Subjects in this study donate blood in a larger content than in daily
practice (circa 50 ml per day with a maximum of 300 ml for 6 days for lung
patients as well for heart transplantation patients). At 1, 3 and 6 months an
additional 2,5 ml serum per time will be withdrawn. No interventions will be
made. No supplementary pain will be caused by extra blood sampling or by urine
collection since intensive care patients are already equipped with an arterial
line and a urine catheter after lung or heart transplantation and blood
sampling in outpatients is standard procedure. Minimal risk is suspected in
research subjects.


Benefit: Due to its completeness, this study will be of substantial value for
transplantation patients. With the novel knowledge acquired with this study we
expect to be able to tailor tacrolimus administration in heart and lung
transplantation patients. The result will be less side and toxic effects, and
thus an increased patient*s safety.