Highlights
- •The burden of drug interactions in CF will increase with CFTR modulators.
- •Trikafta®/Kaftrio® (3 CFTR modulators) has many significant drug interactions.
- •Dose adjustments, avoiding some combinations and monitoring are often required.
- •Evidence gaps: theoretical interactions, clinical significance, management efficacy.
Abstract
The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®,
Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic
fibrosis patients. These drugs have complicated metabolic profiles that make the potential
for drug interactions an important consideration for prescribers, care providers and
patients. Prolonged survival also increases risk of age-related disease and their
associated pharmacotherapy, further increasing the risk of drug interactions and the
need for increased vigilance amongst care providers. We systematically searched the
literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic
drug interactions involving the components of Trikafta®/Kaftrio®. We also searched
electronic databases of drugs for possible drug interactions based on metabolic profiles.
We identified 86 potential drug interactions of which 13 were supported by 14 studies.
There is a significant need for research to describe the likelihood, magnitude and
clinical impact of the drug interactions proposed here.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Cystic FibrosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cystic fibrosis.Lancet. 2009; 373: 1891-1904
- Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del Allele.N Engl J Med. 2019; 381: 1809-1819
- State of the art on approved cystic fibrosis transmembrane conductance regulator (CFTR) modulators and triple-combination therapy.Pharmaceuticals. 2021; 14: 928https://doi.org/10.3390/ph14090928
TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)[product monograph]. Toronto, Ontario, Canada: 2023;Vertex Pharmaceuticals (Canada) Inc.
European Medicines Agency. Kaftrio [Available from: 2023; https://www.ema.europa.eu/en/documents/product-information/kaftrio-epar-product-information_en.pdf.
- 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: 1940-1948
- Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes.N Engl J Med. 2021; 385 (reply): 2208
- A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele.Am J Respir Crit Care Med. 2021; 203: 1522-1532
- Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data.J Cyst Fibros. 2014; 13: 139-147
- Clinical practice guidelines on G, et al. evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.J Am Diet Assoc. 2008; 108: 832-839
- Cystic fibrosis: triple therapy shows promising results.BMJ. 2019; 367: l6347
- Basic review of the cytochrome p450 system.J Adv Pract Oncol. 2013; 4: 263-268
- Transporter-mediated drug-drug interactions.Pharmacogenomics. 2011; 12: 1017-1037
Agency EM. Kaftrio(R) [Available from:2023;https://www.ema.europa.eu/en/documents/assessment-report/kaftrio-epar-public-assessment-report_en.pdf.
- Drug-drug interactions between ivacaftor and midazolam or rosiglitazone in healthy volunteers.J Cystic Fibros. 2012; 11 (SUPPL): S67
- The effect of ciprofloxacin, itraconazole, and rifampin on the pharmacokinetics of lumacaftor in combination with ivacaftor in healthy individuals.Pediatr Pulmonol. 2014; 49 (SUPPL): 286-287
- Evaluation of the drug-drug interaction potential of rifabutin and elexacaftor/tezacaftor/ivacaftor using a physiologically based pharmacokinetic simulation approach.Pediatr Pulmonol. 2020; 55 (SUPPL): 244
- Metabolomic description of ivacaftor elevating polymyxin B mediated antibacterial activity in cystic fibrosis pseudomonas aeruginosa.ACS Pharmacol Transl Sci. 2020; 3: 433-443
- Chronic beta2AR stimulation limits CFTR activation in human airway epithelia.JCI Insight. 2018; 3e93029https://doi.org/10.1172/jci.insight.93029
- Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, enhances ciprofloxacin activity against pseudomonas aeruginosa.Am J Rhinol Allergy. 2019; 33: 129-136
- Pharmacokinetic and drug-drug interaction profiles of the combination of Tezacaftor/Ivacaftor.Clin Transl Sci. 2019; 12: 267-275
- Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer.Pediatr Pulmonol. 2018; 53: E6-E8
- Ivacaftor therapy in siblings with cystic fibrosis-the potential implications of Itraconazole in dosage and efficacy.Pulm Pharmacol Ther. 2015; 31: 49-50
- Physiologically-based pharmacokinetic-led guidance for patients with cystic fibrosis taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19.Clin Pharmacol Ther. 2022; 111: 1324-1333
- The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers.Br J Clin Pharmacol. 2017; 83: 2235-2241
- Antibacterial properties of the CFTR potentiator ivacaftor.J Cyst Fibros. 2014; 13: 515-519
- Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.J Clin Pharmacol. 2015; 55: 56-62
- Pharmacokinetic interactions between ivacaftor and cytochrome P450 3A4 inhibitors in people with cystic fibrosis and healthy controls.J Cyst Fibros. 2021; 20: e72-e76https://doi.org/10.1016/j.jcf.2021.04.005
- Epub 2021 May 15. PMID: 34006500.
- Testing the face validity and inter-rater agreement of a simple approach to drug-drug interaction evidence assessment.J Biomed Inform. 2020; 101103355
- Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support.Drug Saf. 2015; 38: 197-206
Contreary C.G., Seay J.E. Trikafta overdose in an adolescent female with cystic fibrosis: a case report 2021 [June 30, 2022]. Available from: https://www.medschool.lsuhsc.edu/internal_medicine/docs/January_2021_Poster_Session/Abstracts/jessica_seay_abstract.pdf.
Article info
Publication history
Published online: January 16, 2023
Accepted:
January 11,
2023
Received in revised form:
December 21,
2022
Received:
June 30,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
