Trikafta Dosing and Management in Cystic Fibrosis
For patients aged ≥12 years with cystic fibrosis and at least one F508del mutation, Trikafta (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) should be administered as two tablets once daily in the morning plus one ivacaftor 150 mg tablet every 12 hours in the evening, with mandatory baseline and periodic liver function monitoring every 3 months during the first year, strict avoidance of strong CYP3A inducers, and baseline ophthalmologic examination in pediatric patients. 1
Standard Dosing Regimen
Morning dose: Two fixed-dose combination tablets (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) taken once daily 1
Evening dose: One ivacaftor 150 mg tablet taken approximately 12 hours after the morning dose 1
- This triple-combination regimen provides two CFTR correctors (elexacaftor and tezacaftor) plus one CFTR potentiator (ivacaftor) to address the underlying defect in patients with F508del mutations 2
- The therapy is FDA-approved for patients aged ≥12 years with at least one F508del mutation in the CFTR gene 1
Liver Function Monitoring Requirements
Baseline assessment: Obtain alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin before initiating therapy 2
Follow-up monitoring schedule:
- Every 3 months during the first year of treatment 2
- Annually thereafter in stable patients 2
- More frequently if hepatic abnormalities develop 2
Clinical pitfall: The most common adverse events in clinical trials were headache and rash, but hepatotoxicity requires vigilant monitoring as elevations in transaminases can occur 2
Contraindicated CYP3A Inducers
Absolute contraindications include strong CYP3A inducers that significantly reduce elexacaftor, tezacaftor, and ivacaftor exposure, rendering the therapy ineffective 2
Common strong CYP3A inducers to avoid:
- Rifampin (rifampicin)
- Rifabutin
- Phenobarbital
- Carbamazepine
- Phenytoin
- St. John's wort
Clinical consideration: Even moderate CYP3A inducers may require dose adjustments or careful monitoring, though strong inducers represent absolute contraindications 2
Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh Class A): No dose adjustment required 2
Moderate hepatic impairment (Child-Pugh Class B): Reduce dosing frequency—specific adjustments should follow FDA labeling guidance 2
Severe hepatic impairment (Child-Pugh Class C): Use with caution or avoid; if benefits outweigh risks, use at substantially reduced frequency with close monitoring 2
Cataract Screening Requirements
Baseline ophthalmologic examination: Required in all pediatric patients (aged 12-17 years) before initiating therapy 2
Follow-up examinations: Periodic monitoring during treatment, particularly in pediatric patients, as cataracts have been reported with ivacaftor-containing regimens 2
Clinical rationale: Ivacaftor, a component of Trikafta, has been associated with non-congenital lens opacities in pediatric patients in post-marketing surveillance 2
Clinical Efficacy Supporting This Regimen
The triple combination demonstrates substantial superiority over dual therapy:
- Mean improvement in percent predicted FEV₁ of 10.2 percentage points greater than tezacaftor-ivacaftor alone in F508del homozygous patients 3
- CFQ-R respiratory domain score increased by 15.9 points more than tezacaftor-ivacaftor (p<0.0001) 3
- Sweat chloride concentration decreased by 42.8 mmol/L more than dual therapy (p<0.0001) 3
- Projected median survival of 71.6 years for F508del homozygous patients, representing a 33.5-year increase over best supportive care alone 4
Special Populations
Pregnancy: Continue Trikafta throughout pregnancy in women with at least one F508del mutation, as maternal respiratory benefits outweigh theoretical fetal risks, with no congenital abnormalities reported to date 5
Monitoring during pregnancy: Increase CF clinic visits to monthly during first and second trimesters, then every two weeks in the third trimester 5
Common Pitfalls to Avoid
- Discontinuing therapy during pregnancy: This significantly increases maternal mortality risk, especially when baseline FEV₁ is <50% predicted 5
- Using A1C for diabetes screening: Annual oral glucose tolerance testing (OGTT) starting at age 10 is required, not A1C 5
- Inadequate liver monitoring: Failure to check transaminases every 3 months during the first year can miss hepatotoxicity 2
- Co-prescribing strong CYP3A inducers: This renders Trikafta ineffective and represents an absolute contraindication 2
- Skipping baseline ophthalmologic examination: Pediatric patients require cataract screening before starting therapy 2