Kinetics of ivacaftor at Switch Orkambi Symkevi study

CF is the most prevalent lethal genetic disease in the Caucasian population(1).
It is caused by a disruption in the CFTR gene, which leads to the production of
a dysfunctional or absent CFTR protein. The majority of the CFTR protein is
expressed on the surface of apical epithelial cells, where it regulates
chloride ion transport in and out of the cell (2). A disruptions in the
production or functioning of these ion-channels causes a malfunction in several
organ systems (3). Most predominantly are the pulmonary symptoms like
bronchiectasis, small airways obstruction, and progressive respiratory
impairment. Other affected organs include the liver, pancreas, sweat glands and
vas deferens, leading to a severely limited quality of life and a life
expectancy of approximately 40 years(2-4).

For years the treatment of CF has been mostly symptomatic, but recently the
first drug to directly target the mutation-specific defects of the CFTR protein
has been authorised to the European market. This product, Ivacaftor, is a CFTR
potentiator. It works by increasing the probability of CFTR mediated ion
channel opening at the cell surface and thereby enhancing ion transport(5). The
effectiveness of ivacaftor in CF-therapy has been established in combination
therapy with another class of drugs, the CFTR correctors (6, 7). The CFTR
correctors work by improving the cellular processing of CFTR protein, leading
to an increase in CFTR expression at the cell surface. The two currently
registered CFTR correctors are tezacaftor and lumacaftor(8).

Currently patients in the Netherlands with CF who are homozygous for the
Phe508del mutation are eligible for treatment with lumacaftor/ivacaftor (9),a
combination of ivacaftor and lumacaftor given twice a day. This combination has
shown to be effective in increasing the pulmonary function (increasing FEV1 and
reduced number of exacerbations) and nutritional state (bodyweight)(6). But in
2018 Vertex launched the follow up of lumacaftor/ivacaftor, with a similar
effectiveness profile and an increased safety profile, called Symkevi(8). This
product consists of a combination of twice daily ivacaftor and once tezacaftor.
The expectation is that when tezacaftor/ivacaftor will be available in the
Netherlands a major part of the will lumacaftor/ivacaftor users will switch to
tezacaftor/ivacaftor .

Pharmacokinetics
The half-life of ivacaftor when given with lumacaftor is approximately 9 hours
and with tezacaftor approximately 9.3 hours. The half-life is 155 hours for
tezacaftor and 25 hours for lumacaftor(10, 11).

Ivacaftor is mainly metabolised by CYP3A4 and CYP3A5 into the metabolites
hydroxymethyl-ivacaftor and ivacaftor-carboxylate. The pharmacological activity
of these metabolites is respectively 1/5th and 1/50th of ivacaftor(10, 11).
Because of the metabolism by CYP3A4, the pharmacokinetics of ivacaftor are
known to change when co-administered with a CYP3A4 inducer or inhibitor.
One of the most notable differences between tezacaftor and lumacaftor is the
pharmacokinetic influence on ivacaftor metabolism. Lumacaftor is a strong
CYP3A4 inducer thereby causing an increase in the metabolic rate of Ivacaftor
when co-administered. This leads to lower ivacaftor concentrations (10,12).
Tezacaftor has no inducing effect on CYP3A4 and therefore does not influence
the metabolism of ivacaftor (11, 13).

To bypass the influence of CYP3A4 induction a different Ivacaftor dose is
advised based on the co-administered corrector. When used with lumacaftor the
recommended daily dose of ivacaftor is 500 mg daily (2 x 250 mg) and when
combined with tezacaftor 300 mg (2 x 150 mg)(10, 11). What the effect is of
lumacaftor or tezacaftor on the ivacaftor concentration has not thoroughly been
investigated up until now.

Apart from the effect of the correctors on the ivacaftor concentration, also
little is known about the variability between patients and the impact of
patient characteristics on the ivacaftor concentrations. This stretches the
need for a population-based study into the pharmacokinetics and
pharmacodynamics of ivacaftor.

The serum concentration gives insight in several pharmacokinetic parameters,
dependent on the time of concentration measurement. Most commonly used is the
through concentration, a measurement of the concentration right before the next
administration. The through concentration tells if the drug exposure is
sufficient during the entire time span up until the next administration of the
gift. Nonetheless, the through concentration does not give concluding
information on the pharmacokinetics of a pharmaceutical substance. Therefore,
more measurements are needed at different time intervals. In this study the
main aim will be directed towards the through concentration, but a smaller
group of patients will also be asked for a second peak level blood sample. A
second sample makes it possible to investigate other factors like the half-life
and volume of distribution.

The introduction of tezacaftor/ivacaftor provides an opportunity to gain
insight in the pharmacokinetics of ivacaftor in a real world patient population
and with different co-medication. Knowledge from this study will give insight
into the relation between patient characteristics, co-medication, treatment
response and exposure to CF modulators and could therefore be a start to a more
personalized treatment of CF. The main aim of this study is to investigate the
effect of switching from lumacaftor/ivacaftor to tezacaftor/ivacaftor in a
regular clinical setting on the kinetics and exposure of ivacaftor. The
protocol aims to outline the level of exposure in both regimens. A
pharmacokinetic difference leading to a different level of exposure might be
the case, if a statistically significant difference in through-concentration is
found, taking into account the measured plasma concentration and variation
within.

The data we will gather comprises of:
- Sex
- Age
- Name
- Address
- Through concentrations of tezacaftor, lumacaftor en ivacaftor
- T-max concentrations of tezacaftor, lumacaftor en ivacaftor (only in optional
part)
- Concentrations of hydroxymethyl-ivacaftor andivacaftor-carboxylate
- Lung function
- If available: chloride sweat test
- Height and weight
- BMI (Body Mass Index)
- Kidney function: urea, eGFR, Creatin
- Liver function: ASAT, ALAT, GGT, Alkaline phosfatase, total bilirubin
- Comedication
- Adverse Events that are related to the blood sampling

In this study, we want to investigate the effect of the change in co-medication
from lumacaftor to tezacaftor on the kinetics and exposure levels of ivacaftor
described by the through concentrations

Primary Objective: - the through concentration of ivacaftor

Secondary Objective(s):
- to investigate the effect of the change in co-medication from lumacaftor to
tezacaftor on hydroxymethyl-ivacaftor and ivacaftor-carboxylate concentrations.
- to investigate the serum concentrations and kinetics of tezacaftor in
CF-patients treated with tezacaftor combined with ivacaftor.
- to investigate the serum concentrations and kinetics of lumacaftor in
CF-patients treated with lumacaftor combined with ivacaftor.
- to explore the relation between patient characteristics, co-medication and
serum concentrations of ivacaftor/ lumacaftor/ tezacaftor.

This study is an observational, open-label , multi center, study. Approximately
100 CF-patients will be included. The study will be conducted at the Haga
Teaching Hospital and the UMC Utrecht. Analysis will be performed at the
Apotheek Haagse Ziekenhuizen.

The study will be performed during regular outpatient visits. With the
introduction of tezacaftor/ivacaftor, most of the current lumacaftor/ivacaftor
users will switch to the new therapy. This presents the opportunity for a study
in a real world setting. Subjects included in the study will have used
lumacaftor/ivacaftor for at least one month. After this period, a blood sample
will be taken during a regular visit at the outpatient clinic of the Haga
Teaching Hospital or the UMC Utrecht. This sample will be taken prior to the
lumacaftor/ivacaftor morning dose. Ivacaftor, ivacaftor metabolites and
lumacaftor concentrations will be measured in serum. After switching from
lumacaftor/ivacaftor to tezacaftor/ivacaftor a second blood sample will be
obtained, again during a regular outpatient clinic visit at least six weeks
after starting treatment with tezacaftor/ivacaftor. In the second blood
sample, ivacaftor, ivacaftor metabolites and tezacaftor concentrations will be
measured.

For serum measurement, through levels of the CFTR-modulators will be measured.
Therefore, blood has to be drawn in a window of four hours before the next
lumacaftor/ivacaftor or tezacaftor/ivacaftor administration. Information about
the previous administration, time of blood sampling and whether the last
administration was combined with fat containing food, will all be documented on
the lab form. To make sure through concentrations can be collected, patients
will be asked to withhold their lumacaftor/ivacaftor or tezacaftor/ivacaftor
until after the blood sampling. Subjects will also be asked to take the
medication in a similar way at both visits, e.g. together with fat containing
food. In tezacaftor/ivacaftor therapy the standard dose consists of 125 mg
tezacaftor and 150 mg ivacaftor once daily in the morning (equal to 1 tablet
Symkevi ) and 150 mg ivacaftor once daily in the evening (equal to 1 tablet
Kalydeco). In lumacaftor/ivacaftor therapy the standard dose consists of 400 mg
lumacaftor and 250 mg ivacaftor twice daily (equals 4 tablets Orkambi per
day). It is important to mind the fact that tezacaftor/ivacaftor and
lumacaftor/ivacaftor should both be taken together with fat-containing food.

The SOS study also includes an optional part. Participants will be asked if
they want to participate in this optional part of the study as well. In the
optional study, another blood sample will be taken from the subjects at T-max;
between 3 and 5 hours after the lumacaftor/ivacaftor or tezacaftor/ivacaftor
administration. These blood samples will be taken at the same day the pre-dose
samples are drawn. We aim to include 20 patients in this part of the study.

Other data and patient characteristics described at the study parameters
section will be extracted from the hospital information system HIX and verified
with the subject. Apart from the blood sampling and a possible delay in
administration of the medication, no deviations from standard care are needed
during this study.

MAIN Study:
The burden for participating subjects main study consists of:
- 2 blood draws of 4 ml each, 8 ml in total
- 40 minuten of their time

Risks due to participation are:
- undergoing a venipincture can cause some discomfort and may lead to a bruise
near/on the puncture site

OPTIONAL Study: (additional consent required)

The burden for participating subjects optional study consists of:
- 4 blood draws of 4 ml each, 16 ml in total
- 8 hours and 40 minuten of their time

Risks due to participation are:
- undergoing a venipincture can cause some discomfort and may lead to a bruise
near/on the puncture site