To develop a population pharmacokinetic model of Envarsus in stable liver transplant recipients and to evaluate the effect of CYP3A5*3, CYP3A4*22 and IL-polymorphisms of both donor and recipient on Envarsus pharmacokinetics for initial dose…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
levertransplantatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
a: Population Pharmacokinetic parameters of tacrolimus (Envarsus)
b: PK dependency on CYP3A5*3, CYP3A4*22 and IL genotypes of recipient and of
donor.
Secondary outcome
a: Limited PK samplingmodel for accurate AUC estimation
b: Trough - AUC correlation
c:: Changes in Quality of Life before and after conversion.
Background summary
Prolonged release tacrolimus (Envarsus), is a new formulation of the
calcineurin inhibitor tacrolimus. This product was originally developed to
improve bioavailability and to provide more consistent tacrolimus exposure.
Envarsus has also demonstrated a lower peak (Cmax) and reduced peak-to-trough
fluctuations which is associated with decreased tremor incidence. For this
reason doctors are already prescribing Envarsus for liver transplant
recipients. Its pharmacologically active compound tacrolimus is characterized
by a narrow therapeutic window, and highly variable pharmacokinetics
necessitating Therapeutic Drug Monitoring (TDM) to individualize the dose and
prevent rejection or toxicity such as leukopenia and renal toxicity.
Currently in LUMC in daily routine clinical practice tacrolimus (for every
formulation) is dosed based on a limited sampling AUC. Tacrolimus AUC
correlates better with efficacy and side effects than trough concentrations.
For AUC calculation a population PK model is required. However, at the moment
there is no population pharmacokinetic model available for envarsus in contrast
to prograft and advagraf. Tacrolimus is primarily metabolized by the cytochrome
P450 enzymes CYP3A4 and CYP3A5. Genetic polymorphisms in CYP3A4 and CYP3A5 are
known to cause clinically relevant variability in tacrolimus pharmacokinetics
in solid organ transplantation. Therefore transplant recipients at LUMC are
currently genotyped on a routine basis for CYP3A5 polymorphisms in order to
adjust the initial starting dose. Several studies investigated the role of
genetic variants encoding for CYP3A5 in tacrolimus (prograft and advagraf)
pharmacokinetics in liver transplant recipients but genetic variants were never
investigated in relationship with patients receiving Melt Dose tacrolimus
(Envarsus). Since Envarsus has a more prolonged release than the other
formulations and CYP3A4 enzymes are more expressed in the lower tract of the
intestine the effect of CYP3A4 and CYP3A5 polymorphism might be different
compared to prograft and advagraf . Furthermore evidence is accumulating that
pro-inflammatory cytokines are able to down-regulate CYP enzymes. Interleukin
levels and IL-10, IL-6, IL-18 and TNF-alpha polymorphisms have been associated
with altered tacrolimus pharmacokinetics.
We designed this study protocol to develop a population pharmacokinetic model
of Envarsus in stable liver transplant recipients and to evaluate the effect of
CYP3A5*3, CYP3A4*22 and IL-polymorphisms of both donor and recipient on
Envarsus pharmacokinetics for initial dose differentiation and compare it to
Advagraf (the current standard in liver transplantation). Furthermore, we will
study two secondary objectives:
1. Development of a limited sampling strategy to enable accurate prediction of
Envarsus exposure in liver transplant recipients in an efficient way and to
compare it with widely used Ctrough monitoring and the results of Advagraf.
2. Evaluation Quality of life before and after switch to Envarsus therapy using
validated QOL questionnaires, i.e., Short-Form 36 (SF-36), Multidimensional
Fatigue Index-20 (MFI-20), Euroqol 5D (EQ-5D) and adjusted Liver Disease
Symptom Index (LDSI).
Study objective
To develop a population pharmacokinetic model of Envarsus in stable liver
transplant recipients and to evaluate the effect of CYP3A5*3, CYP3A4*22 and
IL-polymorphisms of both donor and recipient on Envarsus pharmacokinetics for
initial dose differentiation and compare it to the current standard
Advagraf.The first secondary objective is to develop a limited sampling
strategy for accurate AUC estimation of Envarsus. The second secondary
objective is the evaluate quality of life of patients on both tacrolimus
formulations.
Study design
An open-label, prospective conversion PK evaluation study
Study burden and risks
Burden:
In addition to regular care (potential burden)
- completing questionnaires during advagraf and envarsus therapy
- whole pk curve measurement via venapuncture including venflon
- use of Dried Blood Spot technique to sample blood to determine drug exposure
Benefit:
Patients on Advagraf will be converted to Envarsus, which might be accompanied
by less adverse effects based on reduced peak-to-trough fluctuations. This is
associated with decreased tremor incidence. Envarsus based immunosuppressive
therapy has been shown to have an improved bioavailability and provide a more
consistent tacrolimus exposure suggesting an overall benefit for the patients
of conversion. This study has been designed to develop a population
pharmacokinetic model of Envarsus in stable liver transplant recipients to be
able to perform AUC based dosing in the future.
Risks:
Participation within the trial comes with minimal risks (if present).
Monitoring of tacrolimus blood concentration
via fingerprick can result in some discomfort. Venapunctures at the hospital
could eventually result in hematoma.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
1. Patient is recipient of a liver transplant at least 6 months prior to entry into the study.
2. Patients are between 18 and 70 years old.
3. Patient is stable on an Advagraf (tacrolimus) based immunosuppressive regimen for at least 3 months.
4. The Advagraf based immunosuppressive regimen remained unchanged for a minimum of 2 months prior to enrolment.
5. The function of the graft is stable.
6. Patients capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent to participate in the study and at time of conversion.
7. Patients haven*t infections or other complications during inclusion into the study.
Exclusion criteria
1. Patient with infections or other complications during inclusion.
2. Patients with direct bilirubin >10 µmol/L or albumin level outside the clinical reference range.
3. Patients allergic or hypersensitive to tacrolimus
4. Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min at time of screening.
5. Patients with unstable dosing and the concomitant use of medications known to affect the PK profile of tacrolimus at the time of conversion.
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL59447.058.16 |