The development of toxic drug-induced hepatitis in a slow metabolizer with cystic fibrosis
https://doi.org/10.18093/0869-0189-2025-35-2-262-268
Abstract
The increased risk of adverse drug reactions in patients with genetically determined features of drug metabolism is actively studied.
The aim was to demonstrate the importance of taking into account pharmacogenetic features and drug interactions for the treatment of cystic fibrosis.
Results. The article describes a case of toxic hepatitis in an 11-year-old child with cystic fibrosis (genotype F508del/F508del in the CFTR gene) and Gilbert’s syndrome (genotype 7TA/7TA in the UGT1A1 gene), who received targeted therapy with the drug elexacaftor/tezacaftor/ivacaftor + ivacaftor. The adverse reaction was provoked by interactions with other drugs, moderate CYP3A inhibitors (fluconazole and pyrantel) that were self-prescribed without consulting the doctor.
Conclusion. When prescribing other drugs against the CFTR modulator treatment, it is necessary to take into account the interactions between the drugs according to the drug labels and it is advisable to determine the presence of Gilbert’s syndrome because of the lifelong use of targeted therapy.
Keywords
cystic fibrosis,
CFTR modulators,
targeted therapy,
toxic hepatitis,
Gilbert’s syndrome,
pharmacogenetics
Supporting agencies: The study was carried out as part of the research “Development of a medical technology for predicting and assessing the effectiveness and safety of therapy with CFTR modulators for cystic fibrosis” (state registration number: 123052200007-4)
About the Authors
I. R. Fatkhullina
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Irina R. Fatkhullina, Head of the Department, pediatri-
cian, research fellow, Researcher
Cystic Fibrosis Department; Department of Hereditary and Metabolic Diseases; Scientific and Clinical Department of Cystic Fibrosis
115522; ul. Moskvorechye 1; Moscow; 141009; ul. Kominterna 124A, build. 1; Moskovskaya obl., Mytishchi
tel.: (495) 111-03-03
Author ID: 1124891
Competing Interests:
Both authors declare no conflict of interest
E. I. Kondratyeva
Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics”, Ministry of Science and Higher Education of the Russian Federation; State Budgetary Healthcare Institution of the Moscow region “Research Clinical Institute of Childhood”, Healthcare Ministry of Moscow Region
Russian Federation
Competing Interests:
Russian Federation
Elena I. Kondratyeva, Doctor of Medicine, Professor, Deputy Director of the Center, Head of the Department
Cystic Fibrosis Center; Scientific and Clinical Department of Cystic Fibrosis; Department of Genetics of Diseases of the Respiratory System
115522; ul. Moskvorechye 1; Moscow; 141009; ul. Kominterna 124A, build. 1; Moskovskaya obl., Mytishchi
tel.: (495) 324-20-24
Scopus ID: 35196167800; Web of Science Researcher ID: АВВ-9783–2021
Competing Interests:
Both authors declare no conflict of interest
References
1. Southern K.W., Patel S., Sinha I.P., Nevitt S.J. Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis. Cochrane Database Syst. Rev. 2018; 8 (8): CD010966. DOI: 10.1002/14651858.CD010966.pub2.
2. Heijerman H.G.M., McKone E.F., Downey D.G. et al. 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 (10212): 1940–1948. DOI: 10.1016/S0140-6736(19)32597-8.
3. Zemanick E.T., Taylor-Cousar J.L., Davies J. et al. 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 (12): 1522–1532. DOI: 10.1164/rccm.202102-0509OC.
4. Vidal. [Trikafta: Instructions for medical use]. Available at: https://www.vidal.ru/drugs/trikafta [Accessed: January 10, 2025] (in Russian).
5. The Union of Pediatricians of Russia. [Targeted therapy for cystic fibrosis. Methodological recommendations]. 2023. Available at: https://www.pediatr-russia.ru/information/events/program/Таргетная_терапия_МВ_методреком_2023_compressed.pdf [Accessed: January 10, 2025] (in Russian).
6. Ivashkin V.T., Baranovskiy A.Ju., Raihelson K.L. et al. [Drug-induced liver injuries (clinical guidelines for physicians)]. Rossiyskiy zhurnal gastroyenterologii, gepatologii, koloproktologii. 2019; 29 (1): 85–115. DOI: 10.22416/1382-4376-2019-29-1-101-131 (in Russian).
7. Delemos A.S., Foureau D.M., Jacobs C. et al. Drug-induced liver injurywith autoimmune features. Semin. Liver Dis. 2014; 34 (2): 194–204. DOI: 10.1055/s-0034-1375959.
8. The Union of Pediatricians of Russia. [Clinical guidelines: Cystic fibrosis. 2021. Available at: https://mukoviscidoz.org/doc/%D0%9A%D0%A0372.pdf [Accessed: January 10, 2025] (in Russian).
9. Aithal G.P., Watkins P.B., Andrade R.J. et al. Case definition and phenotype standardization in drug-induced liver injury. Clin. Pharmacol. Ther. 2011; 89 (6): 806–815. DOI: 10.1038/clpt.2011.58.
10. Stine J.G., Lewis J.H. Current and future directions in the treatment and prevention of drug-induced liver injury : a systematic review. Expert Rev. Gastroenterol. Hepatol. 2016; 10 (4): 517–536. DOI: 10.1586/17474124.2016.1127756.
11. Leise M.D., Poterucha J.J., Talwalkar J.A. Drug-induced liver injury. Mayo Clin. Proc. 2014; 89 (1): 95–106. DOI: 10.1016/j.mayocp.2013.09.016.
12. Sanabria-Cabrera J., Tabbai S., Niu H. et al. N-Acetylcysteine for the management of non-acetaminophen drug-induced liver injury in adults : a systematic review. Front. Pharmacol. 2022; 13: 876868. DOI: 10.3389/fphar.2022.876868.
13. Perlamutrov Y., Bakulev A., Korsunskaya I. et al. Ademetionine in treatment of drug induced liver injury: an observational study in Russian patients, receiving immunosuppressive therapy for psoriasis. Int. J. Pharmac. Sci. Res. 2014; 5 (12): 1000–1007. DOI: 10.13040/IJPSR.0975-8232.5(12).5163-69.
14. Reichelson K.L., Bueverov A.O., Kondrashina E.A. et al. [Intrahepatic cholestasis in chronic liver diseases and the role of ademetionine in its treatment : A literature review and resolution of the Expert Council]. Rossiyskiy zhurnal gastrojenterologii, gepatologii, koloproktologii. 2024; 34 (4): 20–33. DOI: 10.22416/1382-4376-2024-1167-3098-1 (in Russian).
Supplementary files
Review
For citations:
Fatkhullina I.R., Kondratyeva E.I. The development of toxic drug-induced hepatitis in a slow metabolizer with cystic fibrosis. PULMONOLOGIYA. 2025;35(2):262-268. (In Russ.) https://doi.org/10.18093/0869-0189-2025-35-2-262-268
Views:
170
Email this article 