Introduction
Javygtor (generic name: elexacaftor/tezacaftor/ivacaftor) is a novel triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator approved for the treatment of cystic fibrosis in patients with specific genetic mutations. This fixed-dose combination represents a significant advancement in CF therapy by targeting the underlying defect in CFTR protein function.
Mechanism of Action
Javygtor contains three distinct CFTR modulators with complementary mechanisms:
- Elexacaftor: A CFTR corrector that facilitates cellular processing and trafficking of CFTR to the cell surface
- Tezacaftor: A CFTR corrector that improves CFTR protein maturation and stability
- Ivacaftor: A CFTR potentiator that enhances the channel-open probability of CFTR at the cell surface
Together, these components synergistically increase the quantity and function of CFTR protein at the epithelial cell surface, addressing the fundamental pathophysiology of cystic fibrosis.
Indications
Javygtor is indicated for the treatment of cystic fibrosis in patients aged 2 years and older who have at least one F508del mutation in the CFTR gene. This represents approximately 90% of the cystic fibrosis population.
Dosage and Administration
Standard dosing:- Patients ≥12 years: 2 tablets (elexacaftor 100mg/tezacaftor 50mg/ivacaftor 75mg) taken orally once daily with fat-containing food
- Patients 6-11 years: 1 tablet once daily with fat-containing food
- Patients 2-5 years: 1 packet of granules (elexacaftor 100mg/tezacaftor 50mg/ivacaftor 75mg) once daily with fat-containing food
- Hepatic impairment: Use with caution in moderate to severe impairment
- Renal impairment: No dosage adjustment necessary
- Elderly: Limited data available
Pharmacokinetics
Absorption: Peak plasma concentrations reached within 4-6 hours. High-fat meal increases exposure by approximately 2-3 fold. Distribution: Highly protein bound (>99%). Steady state reached within 3-5 days. Metabolism: Primarily hepatic metabolism via CYP3A enzymes. Elimination: Half-life approximately 20-30 hours. Primarily fecal excretion.Contraindications
- Hypersensitivity to any component of Javygtor
- Concomitant use with strong CYP3A inhibitors
- Concomitant use with strong CYP3A inducers
Warnings and Precautions
- Hepatic toxicity: Monitor liver function before and during treatment
- Cataracts: Pediatric patients should undergo baseline and follow-up ophthalmological examinations
- Drug interactions: Significant potential for interactions with CYP3A modulators
- Pregnancy: Limited human data - use only if potential benefit justifies risk
- Lactation: Decision should be made to discontinue nursing or discontinue drug
Drug Interactions
Major interactions:- Strong CYP3A inhibitors (ketoconazole, itraconazole): Contraindicated
- Strong CYP3A inducers (rifampin, St. John's wort): Contraindicated
- Moderate CYP3A inhibitors (fluconazole): Reduce Javygtor dose
- CYP3A substrates: May require dose adjustment of co-administered drugs
Adverse Effects
Common (≥10%):- Headache (15%)
- Nasal congestion (13%)
- Abdominal pain (12%)
- Diarrhea (12%)
- Rash (11%)
- Increased liver enzymes (10%)
- Hepatic transaminase elevations
- Hypersensitivity reactions
- Cataracts (in pediatric patients)
Monitoring Parameters
- Liver function tests at baseline, every 3 months during first year, then annually
- Ophthalmological examinations in pediatric patients at baseline and annually
- Pulmonary function tests (FEV1)
- Nutritional parameters (BMI, weight)
- Sweat chloride testing (for CFTR function assessment)
- Signs and symptoms of hypersensitivity reactions
Patient Education
- Take medication with fat-containing food to ensure optimal absorption
- Do not crush, break, or chew tablets
- Report any signs of liver problems (jaundice, dark urine, abdominal pain)
- Pediatric patients should have regular eye exams
- Inform all healthcare providers about Javygtor use
- Use effective contraception during treatment
- Store at room temperature in original container
References
1. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819. 2. Heijerman HGM, McKone EF, Downey DG, 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. 3. Javygtor [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2021. 4. Davies JC, Moskowitz SM, Brown C, et al. VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018;379(17):1599-1611. 5. Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. Bethesda, MD: Cystic Fibrosis Foundation; 2023.