Elliot Cystic Fibrosis

Cystic Fibrosis

Inherited, multi-organ system disorder

• Lungs, pancreas, intestines, sinuses, skin, and reproductive organs

Manifests as mucosal obstruction of exocrine glands caused by defective ion transport within epithelial cells

CF gene

Found on chromosome 7

Autosomal recessive inheritance pattern

Codes for the CF-transmembrane conductance regulator (CFTR) protein

CFTR (CF-transmembrane conductance regulator) protein

Membrane ion channel prevalent in secretory epithelial cells of airway, GI tract, sweat glands, and GU system

Functions as a chloride channel

Mutations in the CF gene

Dysfunctional CFTR protein

• Decreases chloride secretion

• Increases sodium reabsorption

  • Alters viscosity of fluid excreted by exocrine glands and mucosal obstruction

Over 1000 mutations exist

The majority of mutations in the CF gene are caused by _____

F508del

A mutant CFTR channel does not move chloride ions, causing _____

Sticky mucus buildup on the outside of the cell

_____ is a hallmark of CF and is the cause of death in 90% of patients

Chronic lung disease

Chronic lung disease presentation in cystic fibrosis

Thick, viscous pulmonary secretions (airway surface liquid)

Impaired mucociliary clearance of mucus and debris (mucus plugging)

Obstruction (air trapping, bronchiectasis, atelectasis)

Chronic airway colonization and infection

Exaggerated neutrophil dominated inflammatory response

Chronic obstruction and inflammation

• Pulmonary hypertension

• Respiratory failure

Early pathogens colonizing the lung in cystic fibrosis

Staphylococcus aureus

Non-typeable Haemophilus influenzae

Pseudomonas aeruginosa

What is the hallmark pathogen of cystic fibrosis?

Pseudomonas aeruginosa

Later pathogens colonizing the lung in cystic fibrosis

Burkholderia cepacia complex

Stenotrophomonas maltophilia

Achromobacter (alcaligenes) xylosoxidans

Fungi (candida, asperfillus)

Nontuberculous mycobacteria

Presentation of pancreatic insuffiency in cystic fibrosis

Impaired sodium and chloride transport results in viscous epithelial secretions and obstruction

• Mild cases → accumulations only in small ducts

• Advanced cases → complete blockage of ducts

Malabsorption of fat, protein, and fat-soluble vitamins

• Failure to thrive (FTT)

• Poor growth

• Fat soluble vitamin deficiency

Obstruction of the pancreas in cystic fibrosis prevents _____

Proper excretion of pancreatic enzymes and sodium bicarbonate into digestive tract

Diagnosis of pancreatic insufficiency in cystic fibrosis

Genotype evaluation

Growth failure

Symptoms (steatorrhea)

Fecal elastase

Treatment of pancreatic insufficiency in cystic fibrosis

Pancreatic Enzyme Replacement Therapy (PERT)

• Products containing various amounts of:

  • Lipase → cleavage of fats

  • Amylase → breakdown of starches

  • Protease → breakdown of proteins

• Dosing is based on the amount of lipase per product

• Products are formulated with a pH sensitive coating to protect them from stomach acid

Multivitamin with ADEK (fat soluble vitamins)

Cystic Fibrosis Related Diabetes

Decrease in pancreatic islet cell function and increase in amyloid deposition leads to insulin deficiency

Associated with greater nutritional failure, increased pulmonary disease, and early death

Affects more than 35% of adults with CF

Drug of choice in cystic fibrosis related diabetes

Insulin

• Oral agents not as effective in improving nutritional and metabolic outcomes

Nutrition changes in cystic fibrosis

22% of adults are underweight

Energy needs are greater

• Weight gain can be seen with daily intake 110-200% calories compared to people without CF

Most common presenting features of patients with cystic fibrosis

Acute or persistent respiratory symptoms

Failure to thrive, malnutrition

Abnormal stools

Meconium ileus, intestinal obstruction

Family history

Signs and symptoms of cystic fibrosis

Pulmonary (obstructive airway disease)

• Tachypnea, dyspnea, chronic cough, sputum production, decreased exercise tolerance, wheezing, crackles, eternal retractions, cyanosis, digital clubbing, barrel chest, recurrent respiratory tract infections

GI

• Steatorrhea, flatulence, abdominal pain

Nutritional

• Failure to thrive, poor weight gain, voracious appetite

Diagnosis of cystic fibrosis

Can present with symptoms or a positive family history

>70% of diagnoses are made by 12 months, almost all are made by age 12

“The Sweat Test”

Genetic testing is done to confirm diagnosis and direct treatment, screen in utero, or detect carrier status

The sweat test for diagnosis of cystic fibrosis

Based on 2 separate elevated sweat chloride concentrations at 60 mmol/L or greater obtained through pilocarpine iontophoresis

• < 39 mmol/L → CF unlikely

• 40-59 mmol/L → CF possible

• > 60 mmol/L → Diagnosis of CF

Newborn screenings for cystic fibrosis

Allows for diagnosis before symptoms

Tests for the immunoreactive trypsinogen (IRT) level

• High levels indicated CF (90-95% sensitive)

• Screens for risk only

• Positive result requires referral

Prognosis of cystic fibrosis

Life limiting disorder

Treatment advances have increased median survival from mid teens in the 1970s to > 40 years for patients in the 1990s

Should not limit a child’s ability to attend school and participate in activities

Due to higher age of survival there is now a need to improve transitioning care from pediatric to adult care

Need to ensure patients receive appropriate psychological support to allow patients to cope

Problems that need to be treated in pulmonary treatment

Viscous epithelial secretions

Inflammation

Chronic colonization with bacteria

Treatment goals for cystic fibrosis

Delay disease progression and optimize QOL

• Reduce airway inflammation and infection (acute exacerbations)

• Maximize nutritional status

Nonpharmacologic treatment of cystic fibrosis

Airway Clearance Techniques (ACT)

• Maintenance → 1-2 times/day

• Acute exacerbation → 3-4 times/day

• Loosens thick, sticky mucus, helps with expectoration

• Combine with other treatments

• Bronchodilators should be used before or with ACT

• After ACT, airways are open, administer inhaled antibiotics 

Chest Physical Therapy (CPT)

• Traditional form → percussion and postural drainage

• Oscillating Positive Expiratory Pressure (PEP)

• High Frequency Chest Compression (HFCC)

Pharmacologic treatment classes used in cystic fibrosis

Aerosolized antibiotics

Mucolytics

Anti-inflammatory agents

Bronchodilators

CFTR modulator therapies

Goal of aerosolized antibiotics in cystic fibrosis

Activity against Pseudomonas aeruginosa

Aerosolized antibiotics used in cystic fibrosis

Tobramycin

Aztreonam

Colistin

Tobramycin inhalation in cystic fibrosis

TOBI

• Spectrum → gram-negative bacilli

• 300 mg q12h

  • Reduce to once daily in renal impairment

• Each dose takes about 15-20 minutes to administer

• 28 days on → 28 days off

• ADRs → Bronchospasm, hoarseness, tinnitus

• Pregnancy Category D

• Do not mix with other drugs in nebulizer

TOBI Podhaler

• 112 mg q12h

• Each dose takes about 5 minutes to administer

Aztreonam for inhalation in cystic fibrosis

Administer using only an Altera nebulizer system

75 mg TID via nebulizer

• At least 4 hours between doses

• 2-3 minutes per dose

28 days on → 28 days off

ADRs → Bronchospasm, sore throat, nasal congestion, fever

Pregancy Category B

Must obtain through a specialty pharmacy

Colistin in cystic fibrosis

Not preferred

Parental formulation used by aerosolized administration

75-150 mg bid

ADR → Bronchospasm

• Pretreat with SABA and use immediately after reconstitution

Goal of mucolytics in cystic fibrosis

Decrease viscosity of pulmonary secretions

Increase clearance of sputum

Mucolytics used in cystic fibrosis

Dornase alfa

Hypertonic saline

Mechanism of dornase alfa

CF lungs contain purulent airway secretions composed primarily of highly polymerized DNA from the nuclei of degenerating neutrophils

The presence of DNA produces a viscous mucus with decreased mucociliary transport and infection

Dornase alfa selectively cleaves DNA, reducing mucus viscosity

Results in improved airflow and decreased risk of bacterial infection

Dornase alfa in cystic fibrosis

DNA enzyme produced by recombinant technology

Improves airflow and decreases risk of bacterial infection

2.5 mg inhaled once daily via nebulizer

• Patients > 21 years with FVC > 85% may benefit from BID dosing

Does not significantly reduce risk of pulmonary infections in patients with FEV₁ < 40%

ADRs → change in or loss of voice, rhinitis, sore throat, red watery eyes, runny nose, angina, dyspnea, rash

• Significant → wheezing, chest tighness, fever, pruritis, cough, seizures, swelling of face, lips, tongue, or throat

Do not mix with any other drugs in nebulizer, can denature tobramycin

Benefits of dornase alfa in cystic fibrosis

Short term → Improvement of lung functions after 8 days

Long term → Preserves lung function

Hypertonic saline in cystic fibrosis

7% saline solution delivered via nebulizer

Increases volume of fluid on epithelial lining of the airway to maintain normal ciliary flow and increased sputum expectoration

Inhale BID via nebulizer

ADRs

• Bronchospasm (pre-treatment with SABA necessary)

• Increased coughing, sore throat, chest tightness

• First dose typically administered at physician’s office to ensure no problems

Anti-inflammatory agents used in cystic fibrosis

Inhaled corticosteroids

Oral corticosteroids

Oral NSAIDs

Azithromycin (oral)

Leukotriene modifiers

Inhaled corticosteroids in cystic fibrosis

Used for reactive airways to decrease inflammation

Consider administration following airway clearance

Clear benefit not established in CF patients without reactive airway disease

Oral corticosteroids in cystic fibrosis

Long term use

• Benefit lost shortly following discontinuation

• Safety concerns

Short term use

• Helpful in acute exacerbations

• Used in patients with aspergillus colonization (ABPA)

• Limit dose and duration to least necessary

Oral NSAIDs in cystic fibrosis

Benefit not seen immediately

• Requires daily use for years to see full benefit

  • Studies have shown slowed rate of pulmonary decline, does not improve lung function

Dose → 20-30 mg/kg BID

High doses

• Inhibit lipoxygenase pathway leading to decreased neutrophil migration and lysosomal enzymes

Low doses

• Neutrophil migration increases, potentially increasing inflammation

PK monitoring is recommended

ADRs → Stomach upset, increased bleeding (such as nosebleeds)

Oral azithromycin in cystic fibrosis

Anti-inflammatory properties

Decrease sputum production

Preserve lung function and decrease pulmonary exacerbations

Contraindicated in macrolide resistant nontuberculous mycobacteria

Leukotriene modifiers in cystic fibrosis

Leukotrienes may contribute to CF lung disease

• Cysteinyl LTs have been found in increased concentrations in airway secretions of patients with CF

Montelukast can be used in patients with reactive airway disease

• Useful in allergic rhinitis

Bronchodilators used in cystic fibrosis

Beta-2-adrenergic receptor agonists

Inhaled anticholinergic agents

Beta-2-adrenergic receptor agonists in cystic fibrosis

SABAs

• Use in combination with airway clearance to stimulate mucociliary clearance

• Use in combination with other inhaled therapies to prevent bronchospasm

• May see benefit if recurrent wheeze or dyspnea exists

LABAs

• Benefit for patients with recurrent wheeze or dyspnea

Inhaled anticholinergic agents in cystic fibrosis

Ex. Ipratropium

Administered via nebulizer

Act to decrease bronchospasm

CFTR Modulator Therapies used in cystic fibrosis

CFTR Potentiator

• Ivacaftor

CFTR Correctors

• Lumacaftor

• Tezacaftor

• Elexacaftor

CFTR Potentiator

Compound that increases CFTR transporter function

Mechanism of ivacaftor

Potentiates epithelial cell chloride ion transport of defective 97 CF gene mutations cell-surface CFTR protein

• Improves the regulation of salt and water absorption and secretion in various tissues (ex. lung, GI tract)

Ivacaftor in cystic fibrosis

Indicated for patients 1 month and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data

150 mg q12h

• Dose adjutments necessary in patients with hepatic impairment and with concomitant use with CYP3A4 inhibitors

Administer with high-fat containing foods

Avoid grapefruit and Seville oranges

Monitor FEV₁, ophthalmic examinations (pediatrics), ALT/AST

ADRs → headache, skin rash, abdominal pain, diarrhea, nausea, oropharyngeal pain, upper respiratory tract infection, nasal congestion, nasopharyngitis

Mechanism of lumacaftor

Improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface

Lumacaftor/ivacaftor (Orkambi) in cystic fibrosis

Indicated for treatment of CF in patients 1 year and older who are homozygous for the F508del mutation in the CFTR gene

400 mg/250 mg q12h

Dose adjustments necessary in patients with hepatic impairment and patients already maintained on a strong CYP3A4 inhibitor

Administer with fat-containing food

Avoid grapefruit and Seville oranges

Monitor opthalmological examination (pedriatics), ALT/AST, bilirubin, signs and symptoms of respiratory effects

ADRs → GI (nausea, diarrhea), respiratory (changes in respiration, chest discomfort, dyspnea, nasopharyngitis)

Mechanism of tezacaftor and elexacaftor

Facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR to increase the amount of mature CFTR protein delivered to the cell surface

Tezacaftor/ivacaftor (Symdeko) in cystic fibrosis

Indicated for treatment of CF in patients 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence

100 mg/150 mg in the morning and 150 mg ivacaftor in the evening, 12 hours apart

Dose adjustments necessary in patients with hepatic impairment and patients already maintained on a moderate/strong CYP3A4 inhibitor

Administer with fat-containing food

Avoid grapefruit and Seville oranges

Monitor opthalmological examination (pedriatics), ALT/AST, bilirubin, signs and symptoms of respiratory effects

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

• Fewer side effects, fewer drug interactions

Elexacaftor/ivacaftor/tezacaftor (Trikafta) in cystic fibrosis

Indicated for treatment of CF in patients 2 years of age and older who have at least one copy of the F508del mutation in the CF gene OR one of the other CF mutations that are responsive

2 tabs of 100 mg/75 mg/50 mg in the morning and 150 mg ivacaftor at night, 12 hours apart

Dose adjustments necessary in patients with hepatic impairment

Significant drug interactions, requiring dose/frequency adjustment or avoidance

Administer with fat-containing food

Avoid grapefruit and Seville oranges

Monitor opthalmological examination (pedriatics), ALT/AST, bilirubin, signs and symptoms of respiratory effects

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

What order should medications be administered in cystic fibrosis?

1. Open airways/prevent bronchospasm (SABA)

2. Clear mucus (mucolytics)

3. Treat Pseudomonas (inhaled antibiotics)

Pulmonary exacerbations in cystic fibrosis

Intermittent episodes of acute worsening of symptoms

Clinical features

• Increased cough, increased sputum production

• Shortness of breath

• Chest pain

• Loss of appetite, loss of weight

• Fever, fatigue

• Lung function decline

Treatment of pulmonary exacerbations in cystic fibrosis

Chronic therapies

• Continue chronic medications and airway clearance therapies during treatment of pulmonary exacerbations

• Continue chronic medications in a manner considerate of patient specific factors

Mild symptoms

• Oral and inhaled outpatient antibiotic treatment for 14-21 days

Severe infections

• IV antibiotic treatment for 2-3 weeks

• Anti-pseudomonal beta-lactam and aminoglycoside

  • Synergy and delay of resistance

Monitor FEV₁, symptoms, weight every few days

Corticosteroids for treatment of cystic fibrosis exacerbations

Not recommended for chronic management in most patients

Short course of systemic corticosteroids may offer benefit

CF foundation concludes there is insufficient evidence to recommend the routine use of corticosteroids in the treatment of an acute exacerbation

PK considerations for cystic fibrosis patients

Large V_d for many antibiotics

• Increased ratio of lean body mass to total body mass

• Decreased fat stores

Enhanced body clearance

• Increased renal clearance, increased GFR

• Decreased protein binding

• Increased tubular secretion, decreased tubular reabsorption

• Extrarenal elimination

• Increased metabolism

Although most CF patients have shorter half life and larger V_d, some have decreased renal clearance

PK monitoring required