Pharmacokinetics of tacrolimus during pregnancy in kidney and liver transplant recipients.

In clinical practice, tacrolimus is nowadays often the backbone of
immunosuppressive therapy after solid organ transplantation (SOT). Tacrolimus
has a narrow therapeutic window and a high degree of intra- and
inter-individual pharmacokinetic variability. Therefore, therapeutic drug
monitoring (TDM) is routinely performed using whole blood trough levels.
However, whole blood trough levels might not be the optimal method since >85%
of tacrolimus in the blood is bound to erythrocytes and therefore not
therapeutically active. The maternal anatomical and physiological adaptations
to pregnancy might affect the pharmacokinetics of tacrolimus but existing
knowledge on these affects is scarce. Lastly, little is known about the
possible influence of tacrolimus on placental development and exposure to
tacrolimus in the foetus.

The overall aim of the study is to gain more insight in as well as understand
and map the pharmacokinetics of tacrolimus during pregnancy. Therefore, we will
study tacrolimus concentrations in maternal whole blood (routine care) and via
area under the curve measurements (AUC), in maternal plasma, in maternal CD3+ T
lymphocytes, and postpartum in the umbilical cord (foetal compartment), in
breast milk and in the placenta. Moreover, we will study the maternal and
foetal SNPs/genotypes related with tacrolimus clearance and perform maternal
body composition measurements.

In this prospective two-center cohort study all patients who are planning to
become pregnant after a kidney or liver transplantation in the University
Medical Centre Groningen (UMCG) or the Erasmus Medical Center Rotterdam
(Erasmus MC) are eligible for inclusion. Patients will be identified during the
preconception period. The study period is from study inclusion until one year
postpartum. The study procedures consist of extra blood samples taken at
routinely scheduled venepunctures, AUC measurements using dried blood spots
(DBS) via finger pricks at 5 different days (3 finger pricks per day),
assessing body composition via bio-impedance spectroscopy at 5 different
time-points, one extra venepuncture during delivery, collection of umbilical
cord blood and the placenta directly after delivery, collection of foetal
residual blood and collection of two samples of breast milk. Besides one extra
venepuncture during delivery, no extra venepunctures are needed.

The extra burden in this study is limited to an increased amount of drawn blood
volume, for a total of 110 mL per patient. These additional measurements will
be combined with standard clinical care venepunctures, except for the AUCs via
DBS which will require finger pricks at 5 different days (3 finger pricks per
day, e.g. a total amount of 15 finger pricks). This approach is
minimal-invasive and patient-friendly, collecting very small amounts of blood
(typically 50 µL). For patients who will give birth to their offspring in the
UMCG or Erasmus MC, 1 extra venepuncture around time of delivery is required
with a total amount of 4 mL blood (smallest tube size) and the placenta will be
collected (residual material). If a renal allograft biopsy is performed during
the study period, we will collect 25 mL blood via 1 venepuncture and 3 finger
pricks, if feasible. The burden of possible adverse events from these extra
venepunctures is low, since this only includes a superficial and local hematoma
and pain. Patients willing to donate their breast milk would need to deliver a
total amount of 2 mL, on two different time points postpartum.

There is no burden or risk for the offspring of the patients. The only
intervention is a tacrolimus determination and CYP3A genotyping in the
umbilical cord blood, and tacrolimus determination in residual blood in the
first days postpartum if hospitalized and if possible.

Throughout the study, tacrolimus exposure is closely monitored according to
standard care. Tacrolimus dosages are adjusted through pre-dose TDM which is
currently standard care. Dosages will not be adjusted on measurements performed
for the study. Patients included in this study will not have a therapeutic
effect of the measurements and results. All patients will receive identical
care to those not included in this study, therefore this is a low risk study.
The participants have no benefit of participation in the study. The benefit of
this study is that it may provide a pharmacokinetic model which can be used to
give recommendation on tacrolimus treatment during pregnancy in future pregnant
patients. Information about patient characteristics and pregnancy follow-up
will be obtained from the electronic patient record and therefore will also not
burden the patient. Therefore, the benefits outweigh the risks.