Lumacaftor Ivacaftor

Lumacaftor Ivacaftor Brand Name– ORKAMBI

What is Lumacaftor Ivacaftor

Lumacaftor ivacaftor is an orally available ion channel modulator approved for the treatment of cystic fibrosis (CF) in patients who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The F508del mutation is the most frequent genotype in patients with CF; approximately 45% of CF patients are homozygous for this allele.

Ion channel modulators, such as ivacaftor; lumacaftor, aim to correct the underlying cellular defect (chloride ion transport) responsible for CF instead of the severity of symptoms.

Although neither ivacaftor or lumacaftor monotherapy have shown clinical benefit in patients homozygous for the F508del mutation, clinical trials have demonstrated the combination corrector and potentiator treatment increases forced expiratory volume (FEV1), reduces pulmonary exacerbation rates, and decreases sweat chloride concentrations (a measure of CFTR function) in these patients when compared to placebo.

During Phase 3 trials in patients 12 years and older (n = 1,108), mean improvement in FEV1 ranged from 2.6% to 4% in patients treated with lumacaftor; ivacaftor (p less than 0.001).

Effects on pulmonary function were evident by 2 weeks and significant effects were maintained throughout the 24-week trial period.

Pooled analysis showed the rate of pulmonary exacerbations was 30% to 39% lower in the active treatment group; events leading to hospitalization or the use of intravenous antibiotics were also lower in the treatment group.

Changes in sweat chloride at 8 weeks were modest (-10.3 mmol/L for patients 12 years and older receiving lumacaftor 400 mg/ivacaftor 250 mg twice daily) but significant compared to the placebo group during Phase 2 trials.

In patients 6 to 11 years old (n = 58) receiving lumacaftor 200 mg/ivacaftor 250 mg twice daily, the reduction in sweat chloride at day 15 (-20.4 mmol/L) was sustained through week 24 (-24.8 mmol/L).

The absolute change in sweat chloride from week 24 at week 26 following the 2-week washout period was 21.3 mmol/L.

The efficacy of lumacaftor ivacaftor in patients 6 to 11 years old is extrapolated from efficacy in patients ages 12 years and older. Safety data were obtained from a 24-week Phase 3 clinical trial in patients 6 to 11 years old (n = 58). In patients 2 to 5 years old (n = 60) receiving either lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg twice daily, the reduction in sweat chloride at week 4 was sustained through week 24 (-31.7 mmol/L).

The absolute change in sweat chloride from week 24 at week 26 following the 2-week washout period was 33 mmol/L. The safety profile in patients 2 to 5 years was similar to that in patients aged 6 years and older.

Although the results are modest, lumacaftor; ivacaftor offers a treatment option for patients with the most common mutation associated with CF.

Serious adverse reactions related to elevated liver transaminases have been reported in patients receiving lumacaftor; ivacaftor and, in pediatric patients, ivacaftor has been associated with the development of cataracts. Hence, liver function monitoring and eye exams (pediatric patients) are required at baseline and periodically throughout therapy.

Indications

  • cystic fibrosis

Side Effects

  1. abdominal pain
  2. amenorrhea
  3. cataracts
  4. cough
  5. diarrhea
  6. dysmenorrhea
  7. dyspnea
  8. elevated hepatic enzymes
  9. fatigue
  10. flatulence
  11. headache
  12. hemoptysis
  13. hepatic encephalopathy
  14. hyperbilirubinemia
  15. hypertension
  16. infection
  17. influenza
  18. menorrhagia
  19. menstrual irregularity
  20. nasal congestion
  21. nausea
  22. pharyngitis
  23. rash
  24. rhinorrhea

Monitoring Parameters

  • blood pressure
  • LFTs
  • ophthalmologic exam

Contraindications

  • breast-feeding
  • cataracts
  • children
  • hepatic disease
  • hepatic encephalopathy
  • infants
  • neonates
  • organ transplant
  • pregnancy
  • renal disease
  • renal impairment
  • severe lung dysfunction

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