CFTR combinations

Overview
CFTR combination therapies pair a CFTR potentiator with one or more CFTR correctors to target the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in patients with cystic fibrosis (CF). These regimens are mutation-specific and are designed to:

• Correct defective folding/trafficking of CFTR protein (correctors), allowing more channels to reach the cell surface.

• Potentiate the gating function of CFTR channels at the cell surface, improving chloride and bicarbonate transport (potentiator).

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Rationale for Combination

• In common mutations like F508del, the CFTR protein is misfolded and degraded before reaching the cell membrane (a trafficking defect) and has reduced channel opening even when present at the surface.

• A corrector improves the quantity of CFTR at the membrane, while a potentiator improves the quality of channel activity.

• Triple combination therapy (two correctors + one potentiator) produces greater functional recovery than single or double therapy.

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Approved CFTR Combination Therapies

1. Lumacaftor/Ivacaftor (Orkambi)

   • Mechanism: Lumacaftor – CFTR corrector; Ivacaftor – CFTR potentiator.

   • Indication: Homozygous F508del mutation (≥1 year old in many regions).

   • Key Notes: Improves lung function (FEV₁), reduces pulmonary exacerbations; strong CYP3A induction by lumacaftor can affect other drugs; causes more respiratory adverse effects initially in some patients.

2. Tezacaftor/Ivacaftor ± Ivacaftor (Symdeko in US / Symkevi in EU)

   • Mechanism: Tezacaftor – CFTR corrector with improved tolerability compared to lumacaftor; Ivacaftor – potentiator.

   • Indication: Homozygous F508del or heterozygous F508del with certain residual function mutations (≥6 years old).

   • Key Notes: Better drug–drug interaction profile and fewer respiratory adverse effects than lumacaftor/ivacaftor.

3. Elexacaftor/Tezacaftor/Ivacaftor + Ivacaftor (Trikafta in US / Kaftrio in EU)

   • Mechanism: Elexacaftor – next-generation corrector; Tezacaftor – corrector; Ivacaftor – potentiator.

   • Indication: At least one F508del mutation (covers ~90% of CF patients); approved for ≥2 years old in many regions.

   • Key Notes: Most effective CFTR modulator regimen to date; substantial improvements in FEV₁, sweat chloride, BMI, and reduced exacerbations; generally well tolerated.

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Dosing

• Lumacaftor/Ivacaftor: Oral tablets every 12 hours with fat-containing food.

• Tezacaftor/Ivacaftor: Fixed-dose morning tablet plus ivacaftor alone in the evening.

• Elexacaftor/Tezacaftor/Ivacaftor: Two tablets (morning) containing all three drugs + one ivacaftor tablet (evening), all with fat-containing food.

• Pediatric dosing is weight-based for younger age groups.

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Contraindications

• Hypersensitivity to any active component.

• Strong caution in severe hepatic impairment; dose adjustments in moderate impairment.

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Precautions

• Monitor liver function tests (ALT, AST, bilirubin) before starting, every 3 months for the first year, then annually.

• Ophthalmologic exams in pediatric patients due to risk of non-congenital lens opacities.

• Be aware of drug–drug interactions, particularly with CYP3A modulators.

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Adverse Effects

• Common: Headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased liver enzymes.

• Lumacaftor-containing regimens: Chest tightness, dyspnea (often transient), blood pressure elevation.

• Rare: Hepatic injury, cataracts (pediatric patients).

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Drug Interactions

• Ivacaftor: CYP3A substrate—adjust with strong/moderate inhibitors (ketoconazole, clarithromycin) and avoid strong inducers (rifampicin, carbamazepine, St John’s wort).

• Lumacaftor: Strong CYP3A inducer—reduces exposure to many drugs (e.g., hormonal contraceptives, azole antifungals, some immunosuppressants).

• Tezacaftor/Elexacaftor: CYP3A substrates—same interaction considerations as ivacaftor.