kaftrio(Trikafta)的禁忌症和用药注意事项？

kaftrio(Trikafta)

It is a new CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapeutic drug, suitable for the treatment of cystic fibrosis (CF) in children and adults aged 2 years and above, and can significantly improve lung function and quality of life.

In 2020, kaftrio was approved in the UK for more than 80% of CF patients over the age of 12, and will be expanded to patients over the age of 6 in 2022.

Contraindications

The contraindications of kaftrio (Trikafta) are currently unclear, but patients with advanced liver disease such as cirrhosis and portal hypertension should use Kaftrio with caution unless the expected benefits outweigh the risks. In addition, it is not recommended to co-administer Kaftrio with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, and carbamazepine, which may reduce the efficacy of Kaftrio.

Medication

1. Elevated transaminases and liver damage: Liver function tests should be performed before starting kaftrio treatment, every 3 months during the first year of treatment, and annually thereafter. If there is a significant increase in liver function tests, such as ALT or AST > 5 times the upper limit of normal (ULN), or ALT or AST > 3 times ULN, or bilirubin > 2 times ULN, administration should be interrupted and laboratory tests should be followed closely until the abnormality disappears.

2. Allergic reactions: For example, angioedema and allergic reactions. If signs or symptoms of severe allergic reactions occur during treatment, kaftrio should be discontinued in time and appropriate anti-allergic treatment should be performed.

3. Combined use with CYP3A inducers: Simultaneous use of strong CYP3A inducers can lead to a significant reduction in the exposure of kaftrio. It is not recommended to use kaftrio with strong CYP3A inducers.

4. Combined use with CYP3A inhibitors: The risk of exposure to kaftrio increases. The dose of kaftrio should be reduced when used concurrently with moderate or strong CYP3A inhibitors.

5. Cataracts: It is recommended that pediatric patients starting treatment with kaftrio undergo baseline and follow-up eye examinations.

Treatment with Kaftrio

When used alone or in combination, the ivacaftor/tezakafor/elicapol composite film sheet can partially restore the basic defects of the CFTR protein to improve transepithelial fluid transport and the viscoelasticity of mucus. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into mucociliary epithelial cells to evaluate the effects of tezacaftor, elexacaftor, and their combination with the synergist ivacaftor on key properties of ASL such as fluid reabsorption, viscosity, protein content, and pH.

Treatment of airway epithelial cells with a deletion of phenylalanine at position 508 of the CFTR gene (F508del) with tezacaftor and elexacaftor significantly improved pericilia fluid composition and reduced fluid reabsorption. KaftrioTM was more effective than the single modulator in improving all evaluated parameters, reaffirming that this combination, recently approved for cystic fibrosis patients 6 years and older with at least one F508del mutation in the CFTR gene, is a valuable tool in the fight against CF.

Kaftrio’s efficacy study data

Research background and purpose

The CFTR modulating therapy Kaftrio/Elexaftor-Tezacaftor-Ivacaftor (ETI) has been widely used since it was approved in the EU in 2020. The purpose of this study was to systematically evaluate the impact of ETI treatment on clinical, biochemical data, and Pseudomonas colonization to demonstrate its efficacy.

Research methods

A prospective single-center study included 69 cystic fibrosis patients aged at least 12 years who received ETIs between September 2020 and November 2021. Clinical and laboratory data were collected for each patient and study visit before and after 24 weeks of ETI treatment. Follow-up status of Pseudomonas aeruginosa (PsA) colonization was assessed by periodic sputum or throat swab samples after one year of treatment.

Research results

Within 24 weeks of treatment, significant improvements in biochemical markers of systemic inflammation such as white blood cell counts, immunoglobulins A, G and M, and albumin levels were observed. ETI treatment proved effective, as measured by improvements in lung function and sweat chloride concentration. Assessment of PsA colonization status showed that after one year of treatment, 36% of cases switched from a positive test to a negative test.

Research conclusion

Kaftrio treatment effectively improved systemic inflammatory parameters and showed promising results in PsA status transition.

References:

Ludovico A, Moran O, Baroni D. Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia. Int J Mol Sci. 2022 Sep 27;23(19):11396. doi: 10.3390/ijms231911396. PMID: 36232697; PMCID: PMC9569604.

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