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CFTR Triple Modulator — Cystic Fibrosis Pregnancy: Limited data — category of use in pregnancy must be discussed with CF specialist; some case reports of successful pregnancy outcomes

Elexacaftor / Tezacaftor / Ivacaftor

Brand names: Kaftrio (with ivacaftor tablets — Kalydeco)

Adult dose

Dose: Kaftrio: 2 tablets (elexacaftor 100 mg / tezacaftor 50 mg / ivacaftor 75 mg) in the morning + 1 ivacaftor 150 mg tablet in the evening
Route: Oral (with fat-containing food)
Frequency: Morning: Kaftrio 2 tablets; Evening: Kalydeco 1 tablet
Max: As per dosing schedule above
Triple combination CFTR modulator for CF with at least one F508del mutation (homozygous or heterozygous with another eligible mutation). Highly effective — ~85% of CF patients eligible. Transforms disease course: improves FEV1 by 14%, dramatically reduces exacerbations, reduces need for IV antibiotics, near-normalises sweat chloride in many patients.

Paediatric dose

Dose: Age-based: 2–5 years — reduced dose granules formulation; 6–11 years — reduced adult dose; ≥12 years — adult dose mg/kg
Route: Oral with fatty food
Frequency: Twice daily (morning + evening doses)
Max: Adult dose from age 12 years
BNFc: licensed from age 2 years. Specific dose formulations (granules) for young children — consult SPC. Licensed for ≥1 F508del mutation from 2 years.

Dose adjustments

Renal

No dose adjustment required in mild-moderate renal impairment

Hepatic

Reduce morning dose to 1 Kaftrio tablet in moderate hepatic impairment; avoid in severe impairment

Paediatric weight-based calculator

BNFc: licensed from age 2 years. Specific dose formulations (granules) for young children — consult SPC. Licensed for ≥1 F508del mutation from 2 years.

Clinical pearls

  • VX445-TEZACAFTOR-IVACAFTOR trial: elexacaftor/tezacaftor/ivacaftor improved absolute FEV1 by 14.3 percentage points vs placebo in F508del heterozygous patients — most effective CF therapy ever
  • Mechanism: elexacaftor + tezacaftor correct CFTR folding/trafficking defect (correctors); ivacaftor potentiates channel gating — triple mechanism for F508del
  • Sweat chloride normalisation: many patients achieve sweat Cl⁻ <60 mmol/L (normal range) — functional CFTR restoration at epithelial level
  • Lung transplant: some patients on waiting list for lung transplant improved sufficiently to be delisted after starting Kaftrio — transformative for disease trajectory
  • LFT monitoring: cases of serious hepatic adverse events reported — check LFTs every 3 months for year 1, then every 3 months ongoing; withhold if ALT >5× ULN
  • NICE TA665: Kaftrio approved for CF patients aged ≥2 years with at least one F508del CFTR mutation

Contraindications

  • CF with no eligible CFTR mutations
  • Hypersensitivity to any component
  • Strong CYP3A4 inducers (contraindicated — avoid rifampicin, carbamazepine, St John's Wort)

Side effects

  • Elevated LFTs (most important — monitor closely)
  • Rash
  • Upper respiratory tract infections
  • Headache
  • Diarrhoea
  • Abdominal pain
  • Blood bilirubin elevation
  • Cataracts (children — monitor annually)

Interactions

  • Strong CYP3A4 inhibitors (azoles) — reduce Kaftrio dose to alternate days + ivacaftor dose adjustment; consult SPC
  • CYP3A4 inducers — CONTRAINDICATED
  • Grapefruit/Seville oranges — avoid (CYP3A4 inhibition)

Monitoring

  • LFTs (every 3 months)
  • FEV1 and lung function quarterly
  • Sweat chloride test (response)
  • Ophthalmology annually (children)
  • Blood pressure
  • Creatine kinase

Reference: BNFc; BNF 90; BNFc; AURORA Trial (Heijerman et al. Lancet 2019); VX-445 Trial (Middleton et al. NEJM 2019); NICE TA665; SPC Kaftrio. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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