Within-patient variability in tacrolimus pharmacokinetics in renal transplant patients treated with different tacrolimus formulations.

Immunosuppressive drugs are amongst the most frequently monitored
pharmaceutical compounds. This broad acceptance of therapeutic drug monitoring
is based on the high between-patient variability in the pharmacokinetics of
these drugs, on the concentration-effect relationship and on the narrow
therapeutic window. The determinants for the high between-patient variability
have extensively been studied.

Within-patient variability is a distinct phenomenon. Physicians and surgeons
who are involved in the post-transplant care for organ transplant recipients
have all experienced how in some patients drug concentrations are within the
therapeutic window most of the time, with little fluctuation, whereas in other
patients drug concentrations seem to be on the move constantly. On average
concentrations seem to be fine, and for the treating physician it is difficult
to decide when to intervene and what to do.

In 2010 Borra et al showed that a high within-patient variability in the
tacrolimus clearance was associated with poor clinical outcome, defined as a
composite end point consisting of graft loss, biopsy-proven chronic allograft
nephropathy and doubling in serum creatinine concentration in the period
between t = 12 months post-transplantation and last follow-up . For 297
patients within-patient variability was calculated for all out-patient visits
between month 6 and month 12. The patients were divided into low and high
within-patient variability groups using the median variability as the cutoff
value. In the group with higher variability significantly more patients reached
the primary outcome compared to patients with below median variability.
Recently investigators from Toronto confirmed these observations .

Fluctuating concentrations apparently put the patient at risk for toxicity in
the case of tacrolimus concentrations above the therapeutic window, and for
acute rejection in the case of drug concentrations below the lower threshold of
the therapeutic window. As a result long-term outcome is impaired in patients
with higher within-patient variability, and this asks for interventions.
Within-patient variability is on the radar now. It is a predictor of poor long
term outcome. Other than high donor age, or poor HLA-match, variability is open
for intervention in the long term management of a transplanted patient.

Envarsus.
Life Cycle Pharma (LCP)-tacrolimus (LCP-Tacro) is a recently registered,
prolonged-release, MeltDose formulation of tacrolimus designed for once-daily
administration (trade name Envarsus®). The MeltDose drug delivery technology is
designed to improve the bioavailability of drugs with low water solubility. The
tablet releases tacrolimus throughout the gastrointestinal tract, and is
absorbed in the more distal parts of the gut, where CYP3A4 metabolism in the
gut wall is less active. As a result the bioavailability of Envarsus is about
30% higher compared to the bioavailability of the traditional twice daily
tacrolimus Prograft formulation.

Pharmacokinetic data show that Envarsus is associated with a lower peak (Cmax)
and with reduced peak-to-trough fluctuations compared to the traditional twice
daily tacrolimus Prograft formulation. Envarsus has an excellent correlation
between Cmin and area under the curve. The PK profile of Envarsus is
characterized by flatter kinetics (i.e., less fluctuation and swing) compared
to twice-daily tacrolimus, resulting in a concentration-time profile that is
more consistently within the therapeutic range/window over 24 h.

Whether or not switching patients from the traditional twice daily tacrolimus
Prograft formulation to the novel Envarsus formulation will reduce
intra-patient variability remains to be shown. Wu et al did find support that
conversion from Prograft to the other once daily tacrolimus formulation
(Advagraf) among kidney transplant recipient leads to a lower within-patient
variability of tacrolimus . Stifft et al switched forty renal transplant
patients from Prograft to Advagraf . They measured AUC values using the dried
blood spot method. Conversion resulted in a significant improvement in
intra-patient CV from 14.1% to 10.9% (P=0.012). In view of the pharmacokinetic
properties of Envarsus the reduction in intra-patient variability following
conversion from Prograft to Envarsus might be even larger.

CYP3A5.
Tacrolimus is metabolized by the CYP iso-enzymes CYP3A4 and CYP3A5. There are
polymorphisms in the genes encoding these enzymes, and several studies have
demonstrated that patients homozygous for the CYP3A5*3 single-nucleotide
polymorphism, which leads to the absence of functional CYP3A5 protein, require
a lower Tac dose compared with patients who express CYP3A5 protein due to the
presence of the CYP3A5*1 allele.

Korean investigators have suggested that not only inter-patient variability but
also intra-patient variability is correlated with CYP3A5 genotype . In healthy
individuals taking tacrolimus as part of a bioequivalence study, CYP3A5
expressers had less intra-patient variability as compared with CYP3A5
non-expressers. This observation was explained by
the fact that in patients without functional CYP3A5 enzyme, the metabolism of
tacrolimus depends exclusively on the activity of CYP3A4. Because the CYP3A4
enzyme is more sensitive to induction and inhibition, CYP3A5 non-expressers
could be more prone to variable tacrolimus clearance over time. However, in a
subsequent study Pashaee et al could not find a significant association between
intra-patient variability of tacrolimus clearance and CYP3A5 genotype .
Additionally, in the study by Stifft et al patients with the Cyp3A5*1/*3
genotype (n=11) had a numerically larger improvement in CV than patients with
the CYP3A5*3/*3 genotype4. Taken together, the effect of CYP3A5 genotype on
intra-patient variability is not completely clear yet.

The primary objective of this study is to investigate if the intra-patient
variability in tacrolimus pharmacokinetics is reduced by switching patients
from maintenance tacrolimus treatment with tacrolimus-Prograft to either
Advagraf or to Envarsus.

Secondary objectives are:
1. Study the correlation between CYP3A5 genotype and intra-patient variability
of tacrolimus clearance.
2. Study the impact of switching from Prograft to either of the once daily
formulations on patient satisfaction and quality of life.
3. Study the influence of age and gender on intra-patient variability.
4. Study the preference of patients for choice of formulation for continuation
after study closure.
5. Study the effect of switching to either of the once daily formulations on
incidence of acute rejection, on renal function and on adverse events.

The study design is a randomized study, in which patients are randomized for
conversion to either Advagraf or to Envarsus. Patients will be studied during
12 months. Within this 12 month period they will be treated with Prograft for 6
months and with a once daily formulation of tacrolimus for 6 months. The order
in which the patient will be using twice daily or once daily tacrolimus will be
randomized. At study entry 50% of the patients will be followed for 6 months in
order to first calculate intra-patient variability in tacrolimus
pharmacokinetics during use of Prograft. After 6 months these patients will be
converted to either of the two once daily formulations. Either of these two
once daily formulations will be taken for 6 months. In the other 50% of the
patients conversion to once daily tacrolimus will be done immediately after
study entry, and they will be switched back to Prograft 6 months later.

Stable, adult kidney transplant recipients (* 12 months post transplantation)
who are suitable for the study and have consented to participate will be
enrolled. Screening for eligibility will be done by the investigators. The
nephrologist in charge of the patient at the out-patient clinic will be
informed in case of eligibility. If the treating nephrologist agrees with
inviting the patient to participate, a patient information form will be sent to
the home address of the patient, 2 weeks prior to the scheduled visit to the
out-patient clinic. At the out-patient visit the in-and exclusion criteria will
be checked, and patients will be asked to sign the informed consent form. This
day is called Study Visit 1.

Prograft will be converted to Advagraf on a 1:1 mg basis. The first Envarsus
dose will be calculated based on an expected 30% dose reduction compared to the
previous formulation. One week after the start of Advagraf or Envarsus the
patient will visit the out-patient clinic again. On this day the patient will
be asked for occurrence of adverse events, and blood checks will be performed,
including a tacrolimus trough concentration. Based on the trough concentration
dose adjustments will be performed, aiming to reach the same tacrolimus trough
concentration as during the Prograft treatment.

Patients will be followed for 12 months. During these 12 months patients will
visit the out-patient clinic with intervals of 4 weeks. At every visit a
tacrolimus trough concentration will be drawn. Patients will be asked at what
time they took the dose the day before the out-patient clinic visit.

At the end of the 12-month follow-up period the intra-patient variability of
the pharmacokinetics of all three formulations will be calculated based on the
tacrolimus concentrations (corrected for dose) obtained for each formulation.
In this study also quality of life will be investigated. The MODIFIED
TRANSPLANT SYMPTOM OCCURRENCE AND SYMPTOM DISTRESS SCALE (MTSOSD-59R)
questionnaire will be filled out by the patients in this study. A validated
Dutch version for this questionnaire is available. Furthermore patients are
asked to fill out a form entitled *Enquête behandelingstevredenheid medicatie*.
Patients will be asked to fill out the two questionnaires at three time points:
at study entry, just prior to the moment of conversion to the other formulation
and at the end of the study.

Patients will be switched from Prograft to Advagraf or to Envarsus.

Patients entering this study have been treated with tacrolimus already for 12
months, with good result. They will continue treatment with tacrolimus, but the
formulation will change. Throughout the study there is a close (monthly) watch
for adequate tacrolimus exposure. As the active drug on all three formulations
is the same this study is considered a low risk study. The study related burden
is largely determined by the monthly visits to the out-patient clinic and by
the questionnaires that need to filled out at 3 time points (max 30 minutes per
time point). The benefit of this study is that it may provide clinicians with
an easy intervention to lower the IPV, which will benefit patients on long term
tacrolimus treatment. Thus, the benefit-risk assessment for this study is
favourable.