Highlights
- •The exocrine pancreatic function of people with cystic fibrosis (pwCF) does not significantly influence the absorption and exposure of ivacaftor.
- •The use of pancreatic enzymes in pancreatic insufficient pwCF does not change the absorption and exposure of ivacaftor.
- •Dosing recommendations as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.
Abstract
Background
Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target
the underlying cause of cystic fibrosis (CF), and show robust treatment effects at
group level. The individual effect however, is variable which might be (partially)
related to differences in drug exposure. The profound influence of fat containing
food compared to fasting on drug exposure gives need to investigate if the exocrine
pancreatic function changes the degree and rate of absorption of ivacaftor and thereby
may contribute to differences in drug exposure.
Methods
Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient
(PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with
tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic
parameters were investigated with and without the use pancreatic enzymes and compared
in each individual.
Results
We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly
between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly
change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor.
Conclusion
The exocrine pancreatic function of pwCF does not significantly influence the absorption
and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change
the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned
in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic
function.
Keywords
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References
- Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.Lancet. 2019; 394: 1940-1948https://doi.org/10.1016/S0140-6736(19)32597-8
- Elexacaftor–Tezacaftor–Ivacaftor for cystic fibrosis with a single phe508del allele.N Engl J Med. 2019; 381: 1809-1819https://doi.org/10.1056/NEJMoa1908639
- Lumacaftor–Ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR.N Engl J Med. 2015; 373: 220-231https://doi.org/10.1056/NEJMoa1409547
- Tezacaftor–Ivacaftor in residual-function heterozygotes with cystic fibrosis.N Engl J Med. 2017; 377: 2024-2035https://doi.org/10.1056/NEJMoa1709847
Kalydeco. Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/productinformation/kalydeco-epar-product-information_en.pdf.
Orkambi. Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/productinformation/orkambi-epar-product-information_en.pdf.
Kaftrio. Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/productinformation/kaftrio-epar-product-information_en.pdf.
Symkevi. Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/productinformation/symkevi-epar-product-information_en.pdf.
- Pharmacokinetic interactions between ivacaftor and cytochrome P450 3A4 inhibitors in people with cystic fibrosis and healthy controls.J Cyst Fibros. 2021 Sep 20; (e72-e76)https://doi.org/10.1016/j.jcf.2021.04.005
- Biochemical assessment of the nutritional status of cystic fibrosis patients treated with pancreatic enzyme extracts.Am J Clin Nutr. 1998; 67: 912-918https://doi.org/10.1093/ajcn/67.5.912
- Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for phe508del.N Engl J Med. 2017 Nov 23; 377: 2013-2023https://doi.org/10.1056/NEJMoa1709846
- PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft excel.Comput Methods Programs Biomed. 2010; 99: 306-314https://doi.org/10.1016/j.cmpb.2010.01.007
- Maldigestion associated with exocrine pancreatic insufficiency: implications of gastrointestinal physiology and properties of enzyme preparations for a cause-related and patient-tailored treatment.Am J Gastroenterol. 1995; 90 (PMID: 7661155): 1383-1393
- Impact of elexacaftor/tezacaftor/ivacaftor on vitamin D absorption in cystic fibrosis patients.Pediatr Pulmonol. 2022 Mar 57; : 655-657https://doi.org/10.1002/ppul.25781
- Persistent recovery of pancreatic function in patients with cystic fibrosis after ivacaftor.Pediatr Pulmonol. 2020 Dec 55; : 3381-3383https://doi.org/10.1002/ppul.25065
- Impact of CFTR modulation on intestinal pH, motility, and clinical outcomes in patients with cystic fibrosis and the G551D mutation.Clin Transl Gastroenterol. 2017 Mar 16; 8 (e81)https://doi.org/10.1038/ctg.2017.10
- Time for a gut check: pancreatic sufficiency resulting from CFTR modulator use.Pediatr Pulmonol. Aug 2019; 4 (5): E16-E18https://doi.org/10.1002/ppul.24353
- Causal evaluation of acute recurrent and chronic pancreatitis in children: consensus from the Insppire group.J Pediatr Gastroenterol Nutr. 2017; 64: 95-103https://doi.org/10.1097/MPG.0000000000001446
- Reduction of recurrence risk of pancreatitis in cystic fibrosis with ivacaftor: case series.J Pediatr Gastroenterol Nutr. 2018; 66: 451-454https://doi.org/10.1097/MPG.0000000000001788
- Energy balance and mechanisms of weight gain with ivacaftor treatment of cystic fibrosis gating mutations.J Pediatr. 2018; 201 (e4): 229-237https://doi.org/10.1016/j.jpeds.2018.05.018
Article info
Publication history
Published online: December 07, 2022
Accepted:
November 30,
2022
Received in revised form:
November 14,
2022
Received:
September 2,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
