Personalized tacrolimus treatment for pediatric kidney transplant recipients by using a dosing algorithm and a once-daily tacrolimus formulation.

Bodyweight-based dosing of the immunosuppressive drug tacrolimus in paediatric
kidney transplant recipients is considered standard care, even though the
available evidence for bodyweight-based dosing is thin. Other factors,
including age, ethnicity, co-medication, cytochrome P450 3A (CYP3A) genotype,
and haematocrit, influence the clearance of tacrolimus significantly. Also, the
human microbiome might affect tacrolimus pharmacokinetics and thus an
individual*s dose requirement. The median time to reach the tacrolimus target
pre-dose concentration (C0) is around 7 days but it may take up to 3 weeks in
some individuals, even with therapeutic drug monitoring (TDM). Underexposure to
tacrolimus is associated with rejection and overexposure to the drug with
toxicity. We have developed and improved a tacrolimus dosing algorithm in our
paediatric kidney transplant recipient population, which bases the starting
dose of tacrolimus on bodyweight and CYP3A5 genotype rather than on bodyweight
alone. In part A of this study, this dosing algorithm will be tested
prospectively in this study to guide the tacrolimus starting dose. Computerized
dosing will then be used to adjust the subsequent tacrolimus doses (once the
patient is in steady state) to maintain patients within the target tacrolimus
exposure range, aiming for an area under the concentration versus time curve
(AUC) of 140-180 ng h/mL on day 9-14 after transplantation. Computerized dosing
will not only be based on historical tacrolimus doses and concentrations, but
also on bodyweight, serum creatinine, CYP3A5 genotype, and haematocrit. In part
B of the study, 4 weeks after transplantation, children will switch from a
twice-daily tacrolimus formulation to a once-daily tacrolimus formulation and a
second AUC0-12 will be measured with the aim to describe the pharmacokinetics
of the once-daily tacrolimus formulation.
The hypotheses are that 1) more patients will be within the target C0 range
(10-15 ng/mL) on day 3 after transplantation (primary endpoint; first
steady-state) using the tacrolimus starting dose algorithm and 2) that more
patients will achieve their target tacrolimus AUC0-8 on day 9-14 after
transplantation (secondary endpoint) by using the computerized follow-up
dosing.

This study has been transitioned to CTIS with ID 2024-511585-36-00 check the CTIS register for the current data.

The key objective is to personalize tacrolimus treatment for children with a
renal transplant by using dosing algorithms to calculate both the individual*s
tacrolimus starting dose and follow-up doses. Secondary aims are evaluating the
role of the gut microbiome in tacrolimus pharmacokinetics, and describing the
tacrolimus pharmacokinetics of a once-daily tacrolimus formulation.

Prospective, multi-centre, single-arm, therapeutic intervention study.

All participants will receive a tacrolimus starting dose based on a dosing
algorithm which takes bodyweight and genetic factors into account, rather than
the standard dose which is based on bodyweight alone. After the first
tacrolimus C0 measurement (day 3), computerized dosing will be used to
determine subsequent doses, rather than standard TDM by a transplant physician.
On day 9-14 an AUC0-8 will be measured as part of standard clinical care. A
stool-sample will be collected prior to transplantation and on the day of the
AUC0-8 measurement (post-operative day 9-14) to evaluate the effect of the gut
microbiome on tacrolimus pharmacokinetics. Four weeks after transplantation,
patients will switch from a twice-daily to a once-daily tacrolimus formulation.
On the day of the switch a C0 and peak concentration (Cmax) will be measured
and two weeks after this switch (after week 6), an AUC0-12 will be measured to
describe the pharmacokinetics of the once-daily tacrolimus formulation and
compare it to the twice-daily formulation.

The extra burden for children in the Sophia Children*s hospital and the Amalia
Children*s hospital for the first part of the study (part A) will include the
collection of one extra blood sample on day 3 post-transplantation (to
determine the tacrolimus peak concentration, Cmax) and the collection of two
stool samples (for determination of the microbiome) during hospitalization. As
all children will have a central venous catheter or an arterial line during
hospitalization, the extra blood sample on day 3 does not require an extra
venepuncture. Four weeks after transplantation, in part B of the study, the
children will switch from a twice-daily to a once-daily tacrolimus formulation.
Before this switch an extra Cmax will be measured using a blood sampling method
of the patient*s choice (fingerprick or venepuncture), and after the switch, an
AUC0-12 will be measured. Apart from the tacrolimus algorithm-based dosing and
the switch to a once-daily tacrolimus formulation, all children will receive
identical care to those not included in the study.