Kalydeco(ivacaftor)是什么药？

Kalydeco (ivacaftor) is the first oral CFTR potentiator approved by Health Canada for the treatment of G551 in the CFTR gene D. Cystic fibrosis (CF) in patients 6 years of age and older with G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R mutations.

About Kalydeco (ivacaftor)

It is a compound preparation developed by Vertex Pharmsinc of the United States.

Kalydeco (ivacaftor) was approved by the U.S. Food and Drug Administration (FDA) on February 12, 2018 for the treatment of cystic fibrosis caused by two copies of the F508del mutation in the transmembrane conductance regulator (CFTR) gene or at least one mutation that is responsive to tezacaftor/ivacaftor, and is suitable for use in patients aged 12 years and above.

The drug is co-packaged with tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets and ivacaftor 150 mg tablets, of which tezacaftor is a new chemical entity.

Efficacy

Kalydeco (ivacaftor) works by prolonging the time that activated CFTR channels remain open, thereby enhancing the regulation of chloride ion and water transport across cell membranes.

Usage and Dosage

Kalydeco (ivacaftor) is a 150 mg tablet. Health Canada’s recommended dose is 150 mg every 12 hours, taken with food containing fat.

Therapeutic efficacy

Kalydeco (ivacaftor) has been shown to be safe and effective in cystic fibrosis (CF) patients ⩾6 years of age with at least one F508del-CFTR allele, but has not been studied in younger children.

Purpose: To evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of Kalydeco (ivacaftor) in CF in children aged 2-5 years.

Methods: In this Phase 3, open-label, two-part study (Part A and Part B), children weighing <14kg and ⩾14kg were treated.

Measurements and Main Results: The primary endpoints of Part A (15-d treatment period) were pharmacokinetics, safety, and tolerability. For Part B (24-week treatment period), the primary endpoints were safety and tolerability; secondary endpoints included pharmacokinetics and absolute change from baseline in sweat chloride concentration at Week 24 and lung clearance index 2.5 (LCI2.5, defined as the number of lung conversions required to reduce end-tidal N2 concentration to 2.5% of the initial value).

Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (f508dEl/minimal functional genotype, n=52 F508del/F508del genotype, n=23) were recruited and dosed. Adverse events occurred in 74 children (98.7%), and the severity of these adverse events were mild (62.7%) or moderate (36.0%).

The most common adverse events were cough, fever, and runny nose. Decreases in sweat chloride concentration and LCI were observed from baseline of 2.5 to week 24. Mean body mass index was within the normal range at baseline and remained stable at week 24.

Conclusions: In this open-label study of children aged 2-5 years, treatment with Kalydeco (ivacaftor) was generally safe and well-tolerated, with a safety profile consistent with that observed in older age groups and resulting in clinically meaningful sweat chloride concentrations and LCI2.5.

Side effects

The most common adverse drug reactions of Kalydeco (ivacaftor) are headache, diarrhea, rash, oropharyngeal pain, nasal congestion, abdominal pain, upper respiratory tract infection, nasopharyngitis, nausea and dizziness.

Notes

1. Elevated aminotransferases (ALT or AST):

The aminotransferases (ALT and AST) should be evaluated before starting Kalydeco (ivacaftor) treatment, every 3 months in the first year of treatment, and annually thereafter. More frequent monitoring of liver function tests should be considered in patients with a history of elevated transaminases.

2. Hypersensitivity reaction:

Allergic reactions have been reported after Kalydeco (ivacaftor) was put on the market. If a hypersensitivity reaction occurs, initiate appropriate treatment.

3. Combined use with CYP3A inducers:

Combined use with strong CYP3A inducers, such as rifampicin and St. John's wort, significantly reduces the exposure of Kalydeco (ivacaftor), which may reduce effectiveness. Therefore, coadministration is not recommended.

4. Cataracts:

Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with Kalydeco (ivacaftor). Baseline and follow-up examinations are recommended for pediatric patients initiating treatment with Kalydeco (ivacaftor).

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