Transcript Cystic Fibrosis

Cystic Fibrosis
Erin McDade, Pharm.D., BCPS
Clinical Pharmacy Specialist
Pediatric Pulmonary Service
Texas Children’s Hospital
Objectives
 Describe the pathophysiology and clinical symptoms
of cystic fibrosis (CF)
 Describe differences in pharmacokinetics between
CF and non-CF children
 List the medications involved in the treatment of CF
 Understand the antimicrobials and unique dosing
strategies used for the treatment of acute pulmonary
exacerbations
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Cystic Fibrosis
•A chronic, progressive congenital metabolic
disorder
•Inherited as a recessive trait, in which secretions
of exocrine (sweat and mucus) glands are
abnormal
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History of CF
1936
Middle Ages
(5th to 15th Century)
Medieval
folklore –
infants with
salty skin
considered
“bewitched
” because
they
routinely
die an early
death
Anderson
develops
description
of CF
symptoms
1938
Dr. Guido
Fanconi first
describes
previously
nameless
condition as
“cystic fibrosis
with
bronchiectasis”
and “cystic
fibrosis of the
pancreas”
di Sant’Agnese
reports that CF
patients
excrete
excessive
amounts of
salt in their
sweat – lead to
the
development
of the sweat
test
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1953
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Tsui and
Riordan of
the Hospital
for Sick
Children in
Toronto
discover the
gene
responsible
for CF
2012
1989
FDA
approval of
the first
CFTR
Potentiator
Epidemiology
•Primary cause of chronic lung disease in children
and adolescents
•Most common life-shortening hereditary disorder
of Caucasians in the U.S.
•Incidence
‐1 in 2,500 live births (U.S.)
‐1 in 20 Americans are carriers
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Epidemiology
•2012 median survival: 41.1 years
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Data from CF Foundation Annual Report, 2011
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Pathophysiology
•Autosomal recessive
disorder
•~25 known CF
causing mutations
‐∆F508 mutation is
most common
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Data from CF Foundation Annual Report, 2011
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Cystic fibrosis transmembrane
regulator (CFTR)
•CFTR protein regulates the transport of
electrolytes and water
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CFTR
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Abnormal CFTR
• Mutations in the CFTR
gene result in little to no
functional CFTR protein
at the cell surface
•End result:
‐Thick, viscous, sticky secretions obstruct glands and
ducts in multiple organs
‐Increased salt content in sweat and other serous
secretions
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Gene Mutations
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www.cftrscience.com Vetrex Pharmaceuticals 2011
Signs and Symptoms
http://www.cftrscience.com/cf_pathophysiology.php
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Lung Disease Progression
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Pathophysiology – Lungs
•Accounts for the majority of morbidity and mortality
‐ >95% of CF patients will die as a result of pulmonary disease
•Accumulation of viscous mucous in the airway
•Bacterial colonization
•Acute exacerbations
•Inflammation
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Pathophysiology – Lungs
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Notorious Bacteria
•Pseudomonas aeruginosa
‐Decline in lung function
‐Increased risk of morbidity and mortality
•Methicillin Resistant Staphylococcus aureus
‐Decline in lung function
‐Increased risk of morbidity and mortality
•Burkholderia cepacia
‐Decline in lung function, can be rapid
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Acute Exacerbations
•Increased sputum
production
•Increased WBC
•Febrile
•Increased cough
•Weight loss
•Dyspnea on exertion
•Decreased pulmonary
function tests
•Changes in sputum
color
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Pathophysiology – Pancreas
Normal pancreas and GI
tract
CF pancreas and GI tract
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Pathophysiology – GI tract
Normal GI tract
CF GI tract
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Pathophysiology – Liver
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Pathophysiology – Reproductive
Tract
Normal male
reproductive tract
CF male reproductive
tract
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Pathophysiology – Skin
•Normally Na and Cl are reabsorbed from the
secreted sweat
•Patients with CF lose large quantities of chloride
(and sodium) in their sweat
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Diagnosis
•Timing of diagnosis
‐ 2/3 by the age of 1
‐ 85% by the age of 6
‐ 90% by adulthood
•Sweat chloride test
‐ + if >60 mmol/L of chloride
•Newborn screening
•Genetic testing
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Pharmacokinetics and CF
•Absorption
•Distribution
•Metabolism
•Elimination
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Pharmacokinetics and CF
•Absorption
•Distribution
•Metabolism
•Elimination
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Absorption
•Altered pathophysiology of the GI tract
‐Gastric acid hypersectretion
‐Bile acid malabsorption
•Controversial if absorption is altered
•Bioavailability is largely unaffected
•Delayed time to Cmax for some drugs
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Pharmacokinetics and CF
•Absorption
•Distribution
•Metabolism
•Elimination
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Distribution
•Hypoalbuminemia and hypergammoglobulinemia
‐No difference in protein binding
•Higher blood volume/kg
•Higher volume of distribution for some drugs
‐mg/kg NOT mg/m2
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Pharmacokinetics and CF
•Absorption
•Distribution
•Metabolism
•Elimination
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Metabolism - Hepatic
•Higher hepatic blood flow
•Phase I reactions
‐CYP 1A2 and CYP 2C8
•Increased activity
•Phase II reactions
‐Glucuronyl transferase, acetyl transferase, sulotransferase
•Increased activity
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Pharmacokinetics and CF
•Absorption
•Distribution
•Metabolism
•Elimination
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Elimination - Renal
•Glomerular filtration rate and tubular secretion
‐Normal
•Renal clearance of many drugs is enhanced
•Mechanism unknown
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Goals of Treatment
•Delay / prevent the development of lung disease
•Promote good nutrition and normal growth
•Recognize and treat complications
•Improve quality of life
•Prolong survival
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Pulmonary Drug Therapy
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Inhaled Bronchodilators
•Beta2-agonist given with airway
clearance BID
‐ Albuterol
•2.5 mg nebulized BID
‐ Levalbuterol
•0.63 mg nebulized BID
•Airway clearance techniques
‐ P&PD
‐ Vest
‐ IPV
‐ Acapella
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Airway Clearance Techniques
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Inhaled Mucolytics
•Decreases viscosity of secretions
‐Dornase alfa (Pulmozyme)
‐7% Hypertonic saline (HyperSal)
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Dornase Alfa (Pulmozyme)
•Mechanism of Action
‐ Hydrolyzes the DNA in sputum
•Dose
‐ 2.5 mL nebulized once daily
•Side effects
‐ Voice alteration, dyspnea, sore throat
•$$$ Expensive
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7% Hypertonic Saline (HyperSal)
•Mechanism of Action
‐Increases hydration of mucus due to osmotic flow
‐Breaks ionic bonds in mucus
‐Improves ciliary beat – expectoration of mucus
•Dose
‐4 mL nebulized BID
•Side effects
‐ Bronchospasm
• Premedicate with a bronchodilator (albuterol/levalbuterol) 15 min. before
treatment
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Prophylactic Inhaled Antibiotics
•Benefits of inhaled antibiotics
‐Limit the number or slow the development of acute
exacerbations (fewer hospital days)
‐Concentrate at the site of infection
‐Limited side effects
‐Improve lung function
‐Minimize Pseudomonas colonization
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Prophylactic Inhaled Antibiotics
•Tobramycin (TOBI Nebs)
‐ 300 mg nebulized BID (28 days on, 28 days
off)
‐ SE: hoarseness, oral thrush, bronchospasm
•Tobramycin (TOBI Podhaler)
‐ 112 mg (four 28 mg caps) BID (28 days on,
28 days off)
‐ SE: cough, foul taste, bronchospasm
•Aztreonam (Cayston)
‐ 75 mg nebulized TID (28 days on, 28 days
off)
‐ SE: pyrexia, bronchospasm,
nasal congestion
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Anti-inflammatory Therapy
•Azithromycin
‐ Not antibiotic prophylaxis
‐ Immunomodulatory properties
‐ Biofilm alteration
‐ Studied in patients with PA
•Dose
‐ Monday, Wednesday, Friday dosing
•<25 kg: 10 mg/kg
•25-40 kg: 250 mg
•≥40 kg: 500 mg
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Anti-inflammatory Therapy
•High dose ibuprofen
•Mechanism of action
‐ Inhibits the migration, adherence, swelling, and aggregation of neutrophils, as
well as the release of lysosomal enzymes
•>5 years old with mild lung disease
•Dose
‐ 20-30 mg/kg/dose BID
•PK monitoring necessary
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Gastrointestinal Drug Treatment
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Vitamin and Mineral Supplementation
• Fat soluble vitamins
‐ADEK
• AquaDEKs
• Source CF (non-formulary)
• Vitamax (only through CF Services Pharmacy)
‐Monitor concentrations every two years
• Vitamin K
‐<1 year: 2.5 mg twice a week
‐>1 year: 5 mg twice a week
• Vitamin D
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Pancreatic Enzymes
•Porcine source
•Protease, Lipase, and Amylase
‐ Prevent malnutrition
‐ Promote weight gain
‐ Decrease GI symptoms
•Adverse effects
‐ Fibrosing colonopathy
•Dosing: 500-2500 lipase
units/kg meal
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Additional Considerations
•Vaccinations
‐Pneumococcal
‐Influenza
•Lung Transplant
‐Prolong survival
•Comparable to non-CF lung transplant patients
‐Rejection, opportunistic infections, reinfection, bleeding
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Treatment of Pulmonary
Exacerbations
•Antibiotics
‐Mild exacerbations
•Oral therapy
‐Moderate – Severe exacerbations or failed oral therapy
•IV therapy, usually inpatient
•Aggressive Airway Clearance
•Maximizing nutrition and ensuring weight gain
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IV Antibiotics
•Treatment depends on culture and sensitivity results
•Current and historical cultures should be considered
•Duration of treatment 10-14 days
‐ Sometimes shorter or longer based on PFT results
•Home IV therapy can be considered
‐ Completion of hospital course
‐ Known compliance
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IV Antibiotics
Organism
Treatment Options
H. influenzae
Cephalosporins, TMP/SMX
MSSA
Nafcillin
Pseudomonas aeruginosa (PA)
Aminoglycoside (Tobra or Amikacin)
plus
Ceftazidime, pip/tazo, ticar/clav, cipro
For MRPA:
Colistin, meropenem, aztreonam
MRSA
Clindamycin, Vancomycin, Linezolid,
doxycycline, TMP/SMX, ceftaroline
Stenotrophamonas maltophilia
TMP/SMX, Levofloxacin, Ticar/Clav
Burkholderia cepacia
TMP/SMX, ceftazidime, meropenem,
minocycline
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Antibiotic Dosing in CF
•Often require higher doses and/or more frequent
dosing
‐ Higher Volume of Distribution
‐ Faster metabolism/elimination
Drug
CF dosing
Non-CF dosing
Tobramycin
3-4 mg/kg q8h OR 10
mg/kg every 24 hours
2-2.5 mg/kg q8h
Ceftazidime
200 mg/kg/DAY divided
q8h
150 mg/kg/DAY divided
q8h
Piperacillin/Tazobactam
400-600 mg/kg/DAY
divided q6h [max 6g/dose]
100 mg/kg every 8 h (<40
kg) or 3-4 g IV every 6h (≥
40 kg) [Max 4 gm/dose]
Ciprofloxacin
40 mg/kg/DAY (Oral) or 30
mg/kg/DAY (IV) [Max
1.2g/DAY]
20-30 mg/kg/DAY (Oral or
IV) [Max 800 mg/DAY]
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Future of Cystic Fibrosis Treatment
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CFTR Potentiators/Correctors
•Ivacaftor (Kalydeco ®)
‐ potentiator
•Ataluren (PTC 124)
‐ allows ribosomal stop codon read through
•VX-809
‐ corrector
•VX-661
‐ corrector
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Ivacaftor (Kalydeco ®)
•CFTR potentiator
•FDA approved in Feb 2012
•Indicated for CF patients ≥6 years old with a G551D
mutation
•MOA:
‐ Increases CFTR protein channel opening
•Facilitates increased chloride transport
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Ivacaftor (Kalydeco ®)
•Dosing
‐150 mg PO BID
•Adverse effects
‐Elevated LFTs, headache, dizziness, rash, nasal congestion
•Drug interactions!
‐CYP 3A4 substrate
‐Decrease dose to 150 mg twice weekly when combined with
strong 3A4 inducers
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Ivacaftor (Kalydeco ®)
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Ramsey B NEJM 2011
Ataluren (PTC 124)
•Facilitates premature
stop codon read
through
•Currently undergoing
phase 3 trials
•Patients with
nonsense mutations
(Class I)
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Summary
•CF is a genetic disorder that results in absent or non-functional
CFTR protein affecting many organ systems
‐ Results in thick, viscous mucus
•Pharmacokinetics differ in the CF population
‐ Higher volume of distribution
‐ Faster metabolism and elimination
•Previous drug treatments targeted symptoms and infectious
organisms
•New and investigational treatments are focused on making the
CFTR protein function properly
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References
• Cystic Fibrosis Foundation. Patient registry 2012 annual report. Bethesda, MD: Cystic Fibrosis
Foundation; 2013
• http://www.cftrscience.com
• Davis P. Cystic Fibrosis. Pediatrics in Review 2001;22:257-264.
• Rowe SM, Miller S, Sorscher EJ. Mechanisms of Disease: Cystic Fibrosis. NEJM 2005;19:19922001.
• Rey E, Treluyer JM, Pons G. Drug Disposition in Cystic Fibrosis 1998;35:313-329.
• Lexi-Comp OnlineTM , Pediatric & Neonatal Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp,
Inc.; January 14, 2014.
• Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al. A CFTR potentiatior
in patients with cystic fibrosis and the G551D mutation. NEJM 2011;365:1663-72.
• Pettit R. Cystic fibrosis transmembrane condunctance regulator- modifying medications: the
future of cystic fibrosis treatment. Annals of Pharmacotherapy 2012;46:1065-75.
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Cystic Fibrosis
Erin McDade, Pharm.D.
Clinical Pharmacy Specialist
Pediatric Pulmonary Service
Texas Children’s Hospital