Cystic Fibrosis 2

What are the bronchodilators?

• B2AR agonists

• Inhaled anticholinergic agents (Ipratropium)

What is the short acting beta-agonist?

Albuterol

• Use in combination w/ airway clearance to stimulate mucociliary clearance

• Used in combination w/ other inhaled therapies to bronchospasm

• May see benefit if recurrent wheeze or dyspnea exists

What is the long acting beta-agonist?

Salmeterol

• Benefit for pts w/ recurrent wheeze or dyspnea

What is the inhaled anticholinergic agent (Ipratropium)?

• Administered via nebulizer

• Act to decrease bronchospasm

What are the CFTR modulator therapies?

• Ivacaftor (Kalydeco)

• Iumacaftor/Ivacaftor (Orkambi)

• Tezacaftor/Ivacaftor (Symdeko)

• Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)

What is Ivacaftor (Kalydeco)?

• Approved in January 2012

• CFTR potentiator

  • Compound that increases CTFR transporter function

What is MOA of Ivacaftor (Kalydeco)?

Potentiates epithelial cell Cl- ion transport of defective G55ID mutant cell-surface CFTR protein

• Improves regulation of salt & water reabsorption & secretion in various tissues (lung, GI tract)

What is indication of Ivacaftor (Kalydeco)?

Pts 4 months & older who have 1 mutation in CFTR gene that is responsive to Ivacaftor potentiation based on clinical &/or in vitro assay data

What is dosing of Ivacaftor (Kalydeco)?

150mg Q12H

• Dosage adjustments necessary in pts w/ hepatic impairment & w/ concomitant use w/ CYP3A4 inhibitors

• Administer w/ high-fat containing foods; avoid grapefruit & Seville oranges

What is monitoring of Ivacaftor (Kalydeco)?

FEV1, ophthalmological examinations (pediatrics), ALT/AST

What is AEs of Ivacaftor (Kalydeco)?

Headache, skin rash, abdominal pain, diarrhea, nausea, oropharyngeal pain, upper respiratory tract infection, nasal congestion, nasopharyngitis

What is lumacaftor/Ivacaftor (Orkambi)?

• Approved July 2015

• CFTR corrector; CFTR potentiator

What is MOA of lumacaftor/Ivacaftor (Orkambi)?

Lumacaftor improves conformational stability of F508del-CFTR, resulting in increased processing & trafficking of mature protein to cell surface

What is indication of lumacaftor/Ivacaftor (Orkambi)?

Treatment of CF in pts 1 year of age & older who are homozygous for F508del mutation in CFTR gene

What is dose of lumacaftor/Ivacaftor (Orkambi)?

Lumacaftor 400mg/ivacaftor 250mg every 12 hours

• Dosing adjustments necessary in pts W/ hepatic impairment & when initiating lumacaftor/ivacaftro in pts already maintained on a strong CYP3A4 inhibitor

• Administer w/ fat-containing foods; avoid grapefruit & Seville oranges

What is monitoring of lumacaftor/Ivacaftor (Orkambi)?

Ophthalmological examinations (pediatrics), ALT/AST, bilirubin, signs & symptoms of respiratory effects

What is AEs of lumacaftor/Ivacaftor (Orkambi)?

GI (nauseas, diarrhea), respiratory (changes in respiratory, chest discomfort, dyspnea, nasopharyngitis)

What is Tezacaftor/ivacaftor (Symdeko)?

• Approved February 2018

• CFTR corrector; CFTR potentiator

What is MOA of Tezacaftor/ivacaftor (Symdeko)?

Tezacaftor facilities cellular processing & trafficking of normal & select mutation forms of CFTR to increase amount of mature CFTR protein delivered to cell surface

What is indication of Tezacaftor/ivacaftor (Symdeko)?

Treatment of CF in pts 6 years of age & older who are homozygous (2 copies) for F508del mutation OR who have at least 1 mutation in CFTR gene that is responsible to Tezacaftor/ivacaftor based on it vitro data &/or clinical evidence

What is dose of Tezacaftor/ivacaftor (Symdeko)?

Tezacaftor 100mg/ivacaftor 150mg in morning & ivacaftor 150mg in evening, 12 hours apart

• Dosing adjustments necessary in pts w/ hepatic impairment & when initiating Tezacaftor/ivacaftor in pts already maintained on a moderate/strong CYP3A4 inhibitor

• Administer w/ fat-containing foods; avoid grapefruit & Seville oranges

What is monitoring of Tezacaftor/ivacaftor (Symdeko)?

Opthalmological examinations (pediatrics), ALT/AST, bilirubin, signs & symptoms of respiratory effects

What is AEs of Tezacaftor/ivacaftor (Symdeko)?

CNS (headache, dizziness), GI (nausea, diarrhea), respiratory (changes in respiration, chest discomfort, dyspnea, nasopharyngitis)

What is Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

• Aprroved October 2019

• CFTR corrector; CFTR potentiator

What is MOA of Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

MOAs listed previously

What is indication of Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

Treatment of CF in pts 2 years of age & older who have at least 1 copy of F508del mutation in CFTR gene (90% of population w/ CF) or 177+ other mutations that are responsive

What is dosing of Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

Trikafta is supplied as 2 separate products packaged together; Elexacaftor/tezacaftor/ivacaftor (orange capsule-shaped tablets) in a fixed-dose combination & ivacaftor (blue capsule-shaped tablets)

• Oral: 2 tablets (each containing Elexacaftor 100mg/tezacaftor 50mg/ivacaftor 75mg per tablet) in morning & 1 ivacaftor 150mg tablet in evening, approximately 12 hours apart

• Dosing adjustments necessary in pts w/ hepatic impairment. Significant drug interactions exist, requiring dose/frequency adjustment or avoidance

• Administer w/ fat-containing foods; avoid grapefruit & Seville oranges

What is monitoring of Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

Ophthalmological examinations (pediatrics), ALT/AST, bilirubin, signs & symptoms of respiratory effects

What is AEs of Elexacaftor, Ivacaftor, Tezacaftor (Trikafta)?

CNS (headache, dizziness), GI (nausea, diarrhea), respiratory (changes in respiration, chest discomfort, dyspnea, nasopharyngitis)

What order should pts administer medications?

• Open airways/prevent bronchospams

  • SABA

• Clear mucus

  • ACT

  • Dornase Alfa

  • 7% hypertonic saline

• Treat pseudomonas

  • Tobramycin

  • Aztreonam

  • Colistin

What are pulmonary exacerbations?

Intermittent episodes of acute worsening of symptoms

What are the clinical features of pulmonary exacerbations?

• Increased cough, sputum production

• Shortness of breath (SOB)

• Chest pain

• Loss of appetite, weight

• Fever

• Fatigue

• Liver function decline

What are the chronic therapies of pulmonary exacerbations?

• Continue chronic medications & airway clearance therapies during tx of pulmonary exacerbations

• Continue chronic medication in a manner considerate of pt specific factors

What is tx for mild symptoms of pulmonary exacerbations?

Oral & inhaled outpatient antibiotic tx for 14-21 days

What is tx for severe infections of pulmonary exacerbations?

IV antibiotic tx for 2-3 weeks

• Anti-pseudomonas beta-lactation & aminoglycoside

  • Synergy

  • Delay of resistance

• Monitor FEV1, symptoms, weight every few days

What is not recommended for chronic management in most pts?

Corticosteroids (oral/inhaled)

• Short course of systemic corticosteroids may offer benefit

  • CF foundation concludes there is insufficient evidence to recommend routine use of corticosteroids in tx of an acute exacerbation of pulmonary disease

What are the PK considers w/ CF pts?

• Large Vd for many antibiotics

  • Increased ratio of lean body mass to total body mass

  • Decreased fat stores

• Enhanced total body clearance

  • Increased renal clearance, GFR

  • Decreased protein binding

  • Increased tubular secretion

  • Decreased tubular reabsorption

  • Extrarenal elimination

  • Increased metabolism

• Although most CF pts have shorter t1/2 & larger Vd, some have decreased renal clearance

• PK monitoring required