The influence of pancreatic function on the pharmacokinetics of ivacaftor in patients with cystic fibrosis

Cystic Fibrosis (CF) is the most common life-shortening hereditary disease
among the Caucasian population. The disease is caused by mutations in the gene
that encodes for the CF transmembrane conductance regulator (CFTR). A
disruption in the production or functioning in the CFTR causes a malfunction in
several organ systems. 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 limited quality of life and a shortened life
expectancy.

Recently, drugs to directly target the mutation-specific defects of the CFTR
protein have been authorised to the market. These are potentiators (ivacaftor)
that enhance CFTR channel gating and correctors (lumacaftor, tezacaftor and
elexacaftor) that correct CFTR misprocessing. In 2018, symkevi, which consists
of a combination of tezacaftor and ivacaftor, has been reimbursed for CF
patients who are homozygous for the Phe508del mutation. Recently, symkevi has
also been registered for CF patients heterozygous for the Phe508del mutation
and a CFTR residual function mutation. Standard daily dosage prescription for
symkevi is one dose of tezacaftor/ivacaftor (100 mg/ 150 mg) in the morning and
one dose of ivacaftor (150 mg) in the evening. The dosing advice is the same
for pancreatic insufficient and pancreatic sufficient patients. The major part
of CF patients is pancreatic insufficient and despite treatment with pancreatic
enzymes, still suffer from fat malabsorption. Administered as an oral dose,
tezacaftor/ivacaftor and ivacaftor are absorbed directly from the gut. It is
advised to administer ivacaftor together with fat containing food, because this
increases the exposure to ivacaftor.

Recently, we investigated the pharmacokinetics of ivacaftor in people with
cystic fibrosis and healthy volunteers (article currently under review). Our
data showed a higher exposure to ivacaftor in healthy people than in CF
patients. All CF patients were pancreas insufficient. Therefore, we hypothesize
that a decreased and slower absorption of ivacaftor due to pancreatic
insufficiency in the CF patients has contributed to the observed difference in
exposure. In this study, the influence of pancreatic function on the absorption
and exposure of ivacaftor in patients with CF will be investigated by comparing
pharmacokinetic parameters of pancreas insufficient CF patients with pancreas
sufficient CF patients. Also, the effect of pancreatic enzyme suppletion on
ivacaftor exposure and absorption in pancreatic insufficient patients will be
examined. We expect that pancreas sufficiency will lead to a higher absorption
and exposure of ivacaftor in CF patients than pancreas insufficiency. This
study aims to gain insight if current dosing advice need to be reconsidered.

Our primary objective of the study is:
- To evaluate if pancreas sufficiency leads to a higher absorption and
exposure of ivacaftor in CF patients than pancreas insufficiency. This will be
done by comparing pharmacokinetic parameters (AUC, Cmax, Tmax and T*) of
pancreatic sufficient patients with pancreatic insufficient patients.


Our secondary objectives are:
- To evaluate if the administration of pancreatic enzymes leads to a higher
absorption and exposure of ivacaftor in pancreatic insufficient CF patients
than no administration of pancreatic enzymes.
- To evaluate the number of adverse events and serious adverse events.

This study will be a single-centre study.

Pancreatic sufficient patients will visit the hospital 2 times and pancreatic
insufficient patients 3 times. All patients will be screened during the first
visit, which takes approximately 2 hours. Blood will be collected at 7 fixed
time points (7x15 ml blood) via a peripheral venous catheter, during the second
and third (if applicable) visit, lasting 8-9 hours each.

We do not consider this study a high-risk study. The drugs that the patients
will take during the study (ivacaftor/tezacaftor and amylase/lipase/protease
(creon 10.000)) are all approved by the FDA and EMA and are already in use by
the patients on a daily basis. In addition, the dose that we use does not
exceed the registered dose. Pancreatic insufficient patients normally use their
pancreatic enzymes before every meal, skipping their enzymes once may result in
short-term mild abdominal symptoms.