Personalized Use of Resources study

Kidney transplantation is in most cases the best treatment for patients with
end-stage renal disease. A significant drawback of renal transplantation is the
need for immunosuppressive drugs as long as the transplant is functioning.
Tacrolimus is important as first line immunosuppressive in kidney
transplantation. In different ethnic groups, polymorphism occurs in the CYP3A5
gene, the so called CYP3A5*1. In the African American patients, the frequency
of CYP3A5*1 is, compared to Caucasians, high. The CYP3A5 gene is partly
responsible for the breakdown of tacrolimus in the body. With the CYP3A5*1, a
higher dose of tacrolimus is required to achieve a normal tacrolimus level.
The transplant population of the AUMC consists of a relative high number of
patients from an African or Caribbean background. Up to now the prevalence of
the CYP3A5*1 allele in this population remains to be clarified.

Currently there are two extended release tacrolimus formulas on the market.
Tacrolimus-Extended-Release (Advagraf) and tacrolimus LCPT (Envarsus). Both
formulas have proven their efficacy. Advagraf is currently used routinely as
first line immunosuppressive drug after transplantation. Envarsus is designed
to be better absorbed via the gastrointestinal tract. Bioavailability is low in
patients who require a high dose Advagraf charactarized by a C/D-ratio <1,05
ng/ml × 1/mg. The use of Envarsus can increase bioavailability by 30%.
Furthermore, the use of LCPT might result in a lower Cmax, less variability in
the trough level, a faster achievement of tacrolimus levels in the therapeutic
range, a lower pill burden and less side effects.

This study has been transitioned to CTIS with ID 2024-515542-16-02 check the CTIS register for the current data.

Primary objective:
The objective is to evaluate if the LCPT dose can be reduced in comparison with
tacrolimus-ER and still achieve similar tacrolimus levels in the therapeutic
range in patients who are tacrolimus who need a relatively high dose of
tacrolimus a C/D ratio < 1.05

Secondary objectives:
- To evaluate if the switch design of the study leads to a lower pill burden;
- To evaluate if the tacrolimus switch leads to less side effects.
-to evaluate if the tacrolimus switch leads to less variability in trough levels
- to evaluate if patients with CYP3A5*1 allele is a factor to consider when
prescribing tacrolimus
-to evaluate differences in Cmax, Tmax and and 24hour AUC levels

This is a prospective, open label, switch design study.

Two treatment arms are used in this study:
- Tacrolimus-Extende-Release (Advagraf);
- Tacrolimus LCPT (Envarsus).

On day 1 the subjects, who are on Advagraf, will be switched to Envarsus in a
rate of 1:0.7 for Advagraf to Envarsus.
Envarsus will then be taken for a period of 3 weeks.
On day 23 all subjects will be switched to their usual dose of advagraf.
At the end of the study, on day 46, the subject have the choice to maintain
Advagraf or be switched to Envarsus again.

Kidney transplantation is in most cases the best treatment for patients with
end-stage renal disease. Tacrolimus is important as a first-line
immunosuppressive treatment for kidney transplants. The CYP3A5 gene is partly
responsible for the breakdown of tacrolimus in the body. In different ethnic
groups, polymorphism occurs in the CYP3A5 gene, leading to CYP3A5*1. In people
with the CYP3A5*1 gene variance, a higher dose of tacrolimus is required to
achieve normal tacrolimus levels.

In this study, 2 registered immunosuppressive agents are used, namely
Tacrolimus-Extended-Release (Advagraf) and Tacrolimus LCPT (Envarsus). People
with the CYP3A5*1 gene variant are expected to require a lower dose of Envarsus
compared to Advagraf to achieve a good drug level. This leads to a lower pill
burden, less side effects and lower toxicity.

Side effects of tacrolimus can be:
- Gastro-intestinal complaints such as abdominal pain, constipation, diarrhea,
nausea, vomiting;
- Thirst and excessive urination;
- Increase in hand tremors;
- Blood urination;
- Transplant kidney pain.

The risks/burden associated with the procedures:
- Blood draw: blood draw may cause some discomfort, bruising, minor infections
or bleeding.


The following procedures are performed:
- Blood draws at all visits;
- Collection of 24-hours urine before all visits;
- Completion of questionnaire at the initial visit only.