Drug information of Elexacaftor, Tezacaftor, and Ivacaftor

Elexacaftor and tezacaftor facilitate the cellular processing and trafficking of normal and select mutant forms of cystic fibrosis transmembrane conductance regulator (CFTR) (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface.

Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface.

Absolute bioavailability

Elexacaftor: 80%

Tezacaftor: Not determined

Ivacaftor: Not determined

Peak plasma time

Elexacaftor: 6 hr

Tezacaftor: 3 hr

Ivacaftor: 4 hr

Peak plasma concentration

Elexacaftor: 8.7 mcg/ml

Tezacaftor: 6.8 mcg/mL

Ivacaftor: 1.2 mcg/mL

AUC

Elexacaftor: 162 mcg⋅h/mL

Tezacaftor: 94.5 mcg⋅h/mL

Ivacaftor: 11.7 mcg⋅h/mL

Time to steady-state

Elexacaftor: Within 14 days

Tezacaftor: Within 8 days

Ivacaftor: Within 3-5 days

Protein bound

Elexacaftor: >99%

Tezacaftor: ~99%

Ivacaftor: ~99%

Vd

Elexacaftor: 53.7 L

Tezacaftor: 82 L

Ivacaftor: 293 L

Metabolism

-Elexacaftor

Primary pathway: CYP3A4/5

Active metabolite: M23-ELX

Metabolite potency relative to parent: Similar

-Tezacaftor

Primary pathway: CYP3A4/5

Active metabolite: M1-TEZ

Metabolite potency relative to parent: Similar

-Ivacaftor

Primary pathway: CYP3A4/5

Active metabolite: M1-IVA

Metabolite potency relative to parent: ~1/6

Half-life

Elexacaftor: 29.8 hr

Tezacaftor: 17.4 hr

Ivacaftor: 15 hr

Clearance

Elexacaftor: 1.18 L/hr

Tezacaftor: 0.79 L/hr

Ivacaftor: 10.2 L/hr

Excretion

Elexacaftor: Feces (87.3%; primarily as metabolites); urine (0.23%)

Tezacaftor: Feces (72%; unchanged or as M2-TEZ); urine (14%; 0.79% unchanged)

Ivacaftor: Feces (87.8%); urine (6.6%)

Cystic fibrosis: Treatment of cystic fibrosis in patients ≥12 years of age who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

2 fixed-dose tablets (elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) PO qAM and 1 ivacaftor 150-mg tablet PO qPM; ~12 hr apart.

-Coadministration with moderate or strong CYP3A inhibitors

-Moderate CYP3A inhibitors

Alternate daily dose between 2 fixed-dose tablets qAM and 1 ivacaftor 150-mg tablet qAM.Do not take an evening dose

-Strong CYP3A inhibitors

Take 2 fixed-dose tablets PO twice weekly, ~3-4 days apart.Do not take an evening dose

Headache ,Upper respiratory tract infection ,Abdominal pain ,Diarrhea ,Rash ,Increased ALT ,Increased AST,Increased BUN ,Nasal congestion ,Rhinorrhea ,Rhinitis ,Influenza ,Sinusitis ,Increased bilirubin ,Flatulence, Abdominal distension , Conjunctivitis ,PharyngitisRespiratory tract infection,Tonsillitis,Urinary tract infection,Increased C-reactive protein , Hypoglycemia , Dizziness , Dysmenorrhea , Acne,Eczema ,Pruritus,

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-Elevated liver transaminases and bilirubin levels observed; 

-Noncongenital lens opacities reported with ivacaftor-containing regimens; 

-Coadministration with moderate or strong CYP3A inhibitors increases systemic exposure of elexacaftor/tezacaftor/ivacaftor.

-Coadministration with strong CYP3A inducers is not recommended.

-Coadministration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.

-Ivacaftor may inhibit CYP2C9; monitor INR if coadministered with warfarin; caution with other CYP2C9 substrates (eg, glimepiride, glipizide).

-Elexacaftor and its active metabolite (M23-ELX) inhibit uptake by OATP1B1 and OATP1B3 in vitro; coadministration may increase exposures of drugs that are substrates of these transporters (eg, statins, glyburide, nateglinide, repaglinide).

-measure liver transaminases and bilirubin  levels before initiating, q3Months during first year, and annually thereafter; consider more frequent monitoring for those with history of hepatic disease; interrupt dosing for significant elevations.

-Hepatic impairment:

Moderate: Not recommended unless benefit exceeds risk; reduce dose by omitting evening ivacaftor 150-mg tab; monitor liver function tests

Severe: Do not use

- ALT or AST >5x ULN, or ALT or AST >3x ULN with bilirubin >2x ULN:Consider benefits and risks of resuming treatment following resolution of transaminase elevations

- Missed dose:

Morning dose: If ≤6 hours since the missed morning dose, take the missed dose as soon as possible and continue the original schedule. If >6 hours since the missed morning dose, take the missed dose as soon as possible and do not take the evening dose. The next scheduled morning dose should be taken at the usual time.

Evening dose: If ≤6 hours since the missed evening dose, take the missed dose as soon as possible and continue the original schedule. If >6 hours since the missed evening dose, do not take the missed dose. The next scheduled morning dose should be taken at the usual time.

- Use with caution in patients with severe renal impairment 

Data is limited and incomplete with use of this combination drug or its individual components to inform a drug-related pregnancy risk; reproductive and developmental studies in rats and rabbits have not shown teratogenicity or adverse developmental effects.