Elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis using tacrolimus, a drug - drug interaction study

Cystic fibrosis is a chronic, hereditary, multi-organ disease caused by absence
or dysfunction of the cystic fibrosis transmembrane conductance regulator
(CFTR) protein. Over the past decade, CFTR protein modulators have been
developed, which improve CFTR function either through potentiation of the
abnormal protein channel at the cell surface (ivacaftor) or through correction
of protein transport to the cell surface (lumacaftor, tezacaftor, elexacaftor);
these treatments have now been approved by the European Medicines Agency and US
Food and Drug Administration for use in people with cystic fibrosis and certain
genotypes. Recent trials show an impressive clinical effect of combination
therapy with elexacaftor plus tezacaftor plus ivacaftor. Heijerman et al.
showed in patients homozygous for the Phe508 del mutation an increase in ppFEV1
of 10 percentage points ([95% CI 7·4 to 12·6], p<0.0001) after 4 weeks of
treatment with elexacaftor/tezacaftor/ivacaftor compared to
tezacaftor/ivacaftor. Also, elexacaftor/tezacaftor/ivacaftor was shown to be
efficacious in patients with cystic fibrosis with Phe508del-minimal function
genotypes, in whom previous CFTR modulator regimens were ineffective. For this
genotype, Middleton et al, showed a 13.8 points higher ppFEV1 at 4 weeks and
13.4 points through week 24 compared to placebo. These results are promising
and show the potential of life changing improvements for these patients.
Although many patients will benefit from treatment with these highly effective
modulators, its use is not recommended for CF patients after solid organ
transplantation because of expected drug-drug interaction.


During their lives, patients with cystic fibrosis suffer from problems in
several organ systems. In some CF patients, a kidney or liver transplantation
is indicated due to severe organ failure. After transplantation these patients
are treated with anti-rejection therapy, mostly tacrolimus, a calcineurin
inhibitor and a substrate of CYP3A4. Co-administration of
elexacaftor/tezacaftor/ivacaftor with tacrolimus is thought to increase the
exposure of tacrolimus and thereby may increase the risk for toxicity (e.g.
nephro- and neurotoxicity and hyperglycaemia) and over-immunosuppression,
especially because tacrolimus is considered a narrow therapeutic index drug. As
a CYP3A4 inhibitor, tacrolimus itself may increase levels of
elexacaftor/tezacaftor/ivacaftor. Currently only one case report has been
published reporting two cases of lumacaftor/ivacaftor in two liver
transplantation patients under tacrolimus(6). Unlike other CFTR modulators,
lumacaftor is a CYP3A4 inducer, leading to decreased tacrolimus levels,
observed in this case report. The drug-drug interaction of
elexacaftor/tezacaftor/ivacaftor with tacrolimus has not been investigated
before. Regarding the robust clinically benefit of
elexacaftor/tezacaftor/ivacaftor in both patients with a phe508del
mutation/minimal function mutation and patients homozygous for the phe508del
mutation, the need to investigate the pharmcokinetic interaction of
elexacaftor/tezacaftor/ivacaftor with other drugs becomes more important. In
this study we aim to investigate the drug-drug interaction when
co-administrating elexacaftor/tezacaftor/ivacaftor and tacrolimus in liver or
kidney transplanted adult CF patients.

Primary Objectives:
To investigate the pharmacokinetic interaction of
elexacaftor/tezacaftor/ivacaftor and tacrolimus in adult CF patients using
tacrolimus after renal or liver transplantation by:
- quantitating the effect of elexacaftor/tezacaftor/ivacaftor on the
bioavailability of tacrolimus in CF patients with a history of liver or kidney
transplantation and current on tacrolimus treatment.
- quantitating the dose adjustment of tacrolimus during co-administration of
elexacaftor/tezacaftor/ivacaftor.

Secondary Objectives:
- To investigate the clinical effect of elexacaftor/tezacaftor/ivacaftor in CF
patients using tacrolimus after renal or liver transplantation.
- To quantitate the exposure to elexacaftor/tezacafor/ivacaftor in week 1, 2, 3
and 4 after starting elexacaftor/tezacaftor/ivacaftor.
- To quantitate the number of side effects (adverse events and serious adverse
events) when when co-administrating the elexacftor/tezacaftor/ivacaftor with
tacrolimus.

Single centre, open label drug-drug interaction study

Elexacaftor/tezacaftor/ivacaftor combination with ivacaftor
(Elexacaftor/tezacaftor/ivacaftor).
All subjects will be treated from day 1 of the study with the standard dose
elexacaftor/tezacaftor/ivacaftor 100mg/50mg/75mg 2 tablets in the morning and
ivacaftor 150 mg 1 tablet in the evening.

Study drug will be administered orally together with a standardized
fat-containing snack and 3 creon tablets.

Study load:
Screening: 1 hour: check in and exclusion criteria, medical history and
informed consent procedure

The other 6 visits will take half a day:
Completing the questionnaire (day -14,1,18 and 28), Measuring vital signs,
physical examination, lung function (day -14,1,18 and 28), sweat test (only day
-14 and day 28), Safety blood test (including liver functions) and blood test
for PK measurements at t = 0 (just before taking tacrolimus), t = 1 hour and t
= 3 hours after taking tacrolimus.

For the safety blood collection,3 tubes of 5ml are required
For the PK sampling, 1 tube of 10ml is required per time point.

During the complete study, the patient will take a small blood sample 3 times a
week via a finger prick (dry blood spot method) and will send this to the
laboratory by mail. This will take about 15 minutes at a time.

With the above mentioned study procedures there are no risks associated.


Because drug interactions are expected, the health of the participants and
their tacrolimus exposure will be closely monitored to ensure that tacrolimus
blood levels are within target ranges. If this is not the case, immediate
consultation will take place with the attending transplant doctor and, if
necessary, a dosage adjustment of tacrolimus will follow.
It is expected that in combination with elexacaftor / tezacaftor / ivacaftor
there is a risk of increased tacrolimus levels in the blood. In addition,
tacrolimus may inhibit the degradation of elexacaftor / tezacaftor / ivacaftor,
possibly resulting in increased elexacaftor / tezacaftor / ivacaftor exposure.
Given the narrow therapeutic window of tacrolimus, it is important to monitor
its exposure closely. We expect to minimize the risks of side effects.