Cystic Fibrosis

Cystic Fribrosis is

A genetic condition caused by a mutation in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein

Epidemiology of CF

Inheratance pattern Autosomal Recessive

1, 3500

1 in 30 indivuals of whites are carriers

Most often affcts white people

CFTR protein funciton facts

CFTR protein is a protein found on secretory epithelial cells

funcitons as na ion channel, moving cholride out of cells

Any organ system that has scretory cell will be affects

1. Sweat glands

2. Pancreas

3. Liver

4. Respirtory System

5. Gastro systme’

6. Reproductive tract

Gold standard for CF testing

Sweat testing

<30 CF unlikely

30-59 intermediate

>60 Diagnostic for CF

Diagnosis of CF tests

Newborn Screening NBS

CFTR variant Panel

Sweat Test

Newborn Screeng NBS facts

Performed in all US states

Heelstick 24-48 hours after birth following by immunoreactice trypsinogen assasy

If positive IRT may be repaeted and remainder of diangnositcf pathway should be completed

CFTR Varient Panel

Test blood sample for common CFTR mutant variats

Non white at increased risk for a falsse negative or screening, cannot rule of CF

Cornter sotne of CF management has been symptomatic management in conjuction with preventions and tratemnt o flung infections in these organs

Sweath Glands

Pancrease

Respirtory system

Gastro sysmem

live

reproductive tract

Pulmonoary manifestion of CF facts

Impaired transport of choloirde across pulmonary epitelium

dehydraiton of airwya lumen surface (mucus)

Ineffective mucolilary clearance due to increase visocityt of mucus

Mucos obstruciton, inflmattion, infeciton

Pulomary scarring (fibrosis) increase lung compliance

Pulomary management strategies

Mucus obstruction - Airway clearance

Inflammation - Azithromycin

Infeciton- inhalaed antibiotics

CF airway clearance AWC guideline

Airqay clearance therapy ACT is recommended to all patiantes

No act is superior to the otehr

ACT should be indiviualized

CF ABC of AWC meds

Albuterol (2-15min)

Hypertonic Saline )20 min)

Dornase Alfa (8-10min)

Albuterol (2-15mins)facts

age: no cutoff

dosing

1. Nebulizer 2.5mg -5mg nebulized BID

2. MDI 1-2 puffs inhaled BID

No improvement in FEV

Patient specific uses

Can help prevent broncospams with other inhaled medicaitons

Hypertonic Saline (20minn) facts

Age 6 and older

Dosing 4ml nebulized

Improvement in lung function

can utilize 3 or 3.5% if unable to tolerate 7%

Broncospasm is common

Dornase ALF (8-10min) facts

age 5 years or older

2.5mg or ml nebulizeed daily

5.8% FEV1 improvement at 6 months (once ddaily dosing)

Some patients may benefit from BID

Must refrigerate and protect from light

CF Azithromycin facts dosing

3 times a week weekly regimen

18 to 36 kg 250 mg monday, wednesday, friday

>36kg 500mg monday, wednesday, friday

CF Azithromycin recommendation for age and condiitons

Patient >6 years of age with chronic P aeruginosa infection

Paitent > 6 years of age not chrnically infected with P aeruginosa

CF Azithromycin purpose

Prevents fomration of chronic Psedomas aeriginosa biofilm fomration

Antifinflammotry activyt inhibity netrophil migreation and decreases produciotn of pro inflammatory mediators

Inhaled antiobiotcs ( chroic ) purpose CF

Patients with CF may additionally recieve inhaled antibiotics as part of a maintenance regimen to eradicate or suppress the growth of bacterial organisms of concern namely Pseudomnonas aruginosa

Eradication

1. indcation: first time or new P aeriguinosa growth on cultures

2. goal remove p aerguginosa from lungs and prevent colonization or symptomatic infection

3. regimen 28 day treatment course 1

Suppression

1. Indication: repeated growth of Pseudomonas aeruginosa on cultures

2. prevent symptomatic infection/irreversible loss of lung function

3. Cycled 28 day treatment course followed by 28 day off treatment period continued

FDA approved inhaled antibiotics

Tobramycin

Aztreonam

These should be admin after airway clearance regimen to ensure antibiotics can optimally reach the lungs

Tobramycin dosing

Inhaled solution 300mg neubilized BID

DPI 112mg 4 capsules inhaled BID

Tobramyicn pearls

Most commonly used for borth eradication and suppressive therapy

FDA approved 6 years and older

Aztreonam dosing

75mg nebulized TID

Aztreonam pearls

Requires specialized nebulizer used more often for suppressive therapy > eradication

FDA approved in 7 years of age and older

When to consider de-escalation airway therapies

Stable on CFTR modulator therapy

Stable or improved FEV1

Minimal respiratory symptoms

No recent pulmonary exacerbations

How to deescalate air way therapies

Reduce or discontinue one therapy at a time

Continue monitoring FEV1 and respiratory symptoms

Reassess before making additional changes

If clinical status worsens airway therapies

Decline in FEV1

Increase cough or sputum

New/worsening respiratory symptoms

Pulmonary exacerbation

restart or intensify airway therapies

Goal of deescalating airway therapies

Reduce treatment burden while maintaining stable lung function

Acute Pulmonary Exacerbations facts

Acute worsening of respirtory symptoms cough, sputum, production, quality change, shortness of breath and decline in FEV1

clnical implicaitons

1. reduced health related quality of life

2. irreversible and progressive loss of lung function

3. increase risk of for future exacerbations

Acute pulmonary excaverations therpuetic goal

Return to baseline FEV1

Acute Pulmonary Exacerbations guideline directed management

Temporally increase maintenance airway therapies

1. airway clearance and albuterol increased to four times per day

2. dornase alfa increased to two times per day

Initiate combination antibiotic therapy (systemic TX)

1. common pathogens Pseudomonas aeruginosa, staff aurea, stenotropmonommas maltophillia

2. Antiobiotic selection based on recent cultures/susceptibilites when available from the previous 6-12 months

Treat with Antibiotic for 10-14 days

1. CF foundation guidelines insufficient evident regaridng ideal duration

2. 10 days not inferior to 14 days

3. 21 days is not superior to 14 days

Acute Pulmonary Exacerbations antibiotic dosing considerations

Volume of distributions

1. Increase VD

2. Seconday to increased amounts of lean tissue per kg of body weight

3. Higher dose often required to achieve goal concentrations

Clearance

1. increase renal and non renal clearance

2. Poorly understood, hypermetabolic state, increased GFR and secretion

3. More frequent dosing required

PK/PD optimization

1. Time dependent ABX beta lactam

   1. lower dose

   2. more frequent dosing and or extended infusion admin

2. Conc dependent ABX aminoglycoside

   1. Higher dose

   2. less frequent dosing safety
      
      

Pseudomonal coverage in CF gold standard

Double Anti Pseudomonal coverage

Anti pseudomonal beta lactam + IV aminoglycoside

Uitlization of two agents with different mechanism of action

1. Add a synergistic effect (attacking the pseudomonas spp from two ways

2. helps avoid resistancce (reduces selective pressure for resistant isolates in this high risk population

No singue antibiotic!!!

The Exocrine Pancreas facts

Role of pancratic exocrine gland c ells secrete digestive enzymes

Alkaline pancreatic fluid functions to

1. solubilize the digestive enzymes

2. Transport digestive enzymes to the duodenum

The creation of alkaline pancreatic fluid is reliant on the secretion of chloride

In CF the secretion of chloride is impaired

Thick, stick mucus replaces the dree flowing pancreatic fluid normally produced

These altered secretions obstruct the pancreatic ducts

Pancreatic Insufficiency symptoms

Pancreatic duct obstruction prevents digestive enzymes from reaching the duodenum

inability to break down carbohydrates, proteins, and fat in the diet
GI upset

Steatorrhea

bloating

flatulence

Weight loss

Malnourishment

Poor growth (children) Normal growth is associated with improved lung function in children with CF

Pancreatic Insufficiency diagnosis

Annual fecal elastase screening

Pancreatic insufficient if fecal elastase < 200 mcg/g

Pancreatic Insufficiency management

High calorie, high fat diet

supplementation of fat soluble vitamins as needed

Pancreatic enzyme replacement therapy (PERT)

Pearls of PERT

Replacement is lifelong

Therapy is formulation specific brands are not interchangeable

1. microencapsulated (enteric coated) are most effective

2. brands differ in terms of amylase/protease components

Dosing

1. Infants weight x 13000 divided by number of feeds day. Max 13000 lipase units

2. Children/adults 2500 lipase units kg meal

3. snacks ½ mealtime dose

PERT medicines list

Zenpep

Creon

Pancreaze

Pertyze

Viokace

Vitamin D supplementation facts

Goal 25 hydroxyvitamin > 30 ng/ml

Vitamin D should be supplemented as cholecalciferol based on patient specific vitamin D level and age

Reassess vitamin D levels 3 months after a change + annually once stable

CF related Diabetes (CFRD) facts

Pancreatic duct obstruction leads to chronic inflammation and intrinsic damage to pancreatic cells including beta cells (insulin)

resluts is insulin insufficiency (cellular damage)+ insulin insensitivity (inflammation)

CF related Diabetes (CFRD) screening

Oral glucose tolerance test annually beginning at 10 years old

Standard ADA criteria

1. Fasting glucose > 126 mg/dl

2. 2 hour glucose > 200 mg/dl

3. A1c > 6.5% although this is often low in CF

CF related Diabetes (CFRD) management

Moderate aerobic exercise 150 minutes a week

Insulin Therapy

1. oral diabetic agents are not as effective in improving nutritional and metabolic outcomes in CFRD

CF related Diabetes (CFRD) monitoring

BG checks 3 per day per ADA recommendations

Quarterly A1c measurements goal < 7%

Annual monitoring for microvascular complications

Lipid profile annually if high risk

CF historical perspective facts

For decades the management of cystic fibrosis consisted soley of supportive care targeting the symptoms and manifestations of the disease. There was no treatment or cure itself

Median survival in 2010 was 39 years

2012 FDA approved the first CFTR modulator therapy while not a cure addresses the cause of the symptoms

Median survival 65 years

CFTR Class I mutations

No functional protien

Production mutation

CFTR Class II mutations

Right protein, wrong place

Processing mutation

Receptor Trafficking Issue

CFTR Class III mutations

Protein functionality Issue

Dysfunctional gate

Gating mutation

CFTR Class IV mutations

Protein Functionality Issue

Dysfunctional channel

conduction mutation

CFTR Class V mutations

Protein Quantity Issue

Everything goes right, just not enough CFTR protein is produced

potentiators (monotherapy) facts

Increases the function of CFTR channels already on the cell surface (conductance of CL)

potentiators (monotherapy) drug

Kalydeco

Kalydeco facts

First CFTR modulator approved (ivacaftor)

Only CFTR therapy that is potentiator only

limitation requires CFTR protein to be synthesized and to some extend transported to cell surface

Not active against Type 1 syntheis or Type II processing defects

DDI CYP3A4 substrate (major)

Combinations Therpay facts

Correctors

Correct misfolded CFTR proteins and increase their processing and trafficking to the cell surface

Combiatino therapy drugs

Orkambi

Symdeko

Orkambi facts

combinatin of lumacaftor + ivacafoor

corrector component provides activity for those with Class II defects

specficially homozygous F508del

DDI

CYP3A4 substrate (major)

CYP3A4 inducer (strong)

Symdeko facts

Combinatino of tezacaftor + ivacaftor

Active against wider range of mutations

± F508del

DDI

Cyp3A4 substrate (major)

Found to have lower indcidence of ADEs than lumacamftor (chest tightness)

Triple Therapy drugs list

Trifafta

Alyftrek

Trikafta facts

Combination of elexacftor 6 tezacaftor + ivacaftor

Addition of a second corrector synergy

521 + eligelble mutations

DDI

CYP3A4 substrate (major)

Alyftrek facts

combination of vanzacaftor + tezafaftor 6 deutivacaftor (Alyftrek)

Synergy effect

564 + eligible mutations

modifid ivacaftor allows for once daily dosing

DDI

CYP3A4 substatge (major)

Triple therapy leads to

Major Increase in FEV1

Ivacaftor (kalydeco) FDA approved age

1> Month

Ivacaftor (kalydeco) # of mutations approved and notable mutations

97

Non Class II

G55D 10% increase FEV1

R117H 5% Increase FEV1

Lumacaftor + Ivacaftor (Orkambi) approved age

>1 year

Lumacaftor + Ivacaftor (Orkambi) # of mutations approved and notable mutations

1

F508del (Class II) x 2

Homozygous F508del (4% FEV1 increase

Tezacaftor + Ivacaftor (Symdeko) approve age

>6 years

Tezacaftor + Ivacaftor (Symdeko) # of mutations approved and notable mutations

155

± F508del

Homozygouus F508del (4% FEV1 increased

Heterozygous F508del 6.8% FEV1 increase

Elexacafotr + Tezacaftor + Ivacafotr (Trikafta) approved age

>2 years

Elexacafotr + Tezacaftor + Ivacafotr (Trikafta) # of mutations approved and notable mutations

At least one CFTR variant that is EITHER responsive based on clinical and or in virtro data or that results in production of CFTR protein

Homo/hetero zygous F508del 10-14% increased FEV1

Similar efficacy for non F508del

Vanzacafotr+ Tezacaftor + Deutivacaftor (Alyftrek) approved age

>6 years

Vanzacafotr+ Tezacaftor + Deutivacaftor (Alyftrek) # of muations approved and notable mutations

At least one CFTR variant that is EITHER responsive based on clinical and or in virtro data or that results in production of CFTR protein

± F508del (similar FEV increase similar to Trifkafta)

CFTR modulation general facts

The impact on FEV1 increases as you go from monotherapy to combo therapy to triple therapay

Combinatinos therapy Orkabmi vs Symdeko comparions

Orkambie

1. Approved for 1 vs 6 years of age

Symdeko

1. Greater # of muations

2. Fewer DDIs

3. Lower ADE incidence

Triple Therapy Trifafta vs Alyftrek

Trikafta

1. Eligible for rare mutations

2. Appoved for 2 vs 6 yeas of age

Alyftrek

1. Eligible for rare muations

2. once daily dosing

Counseling

doses shoulb be taken with a high fat snack or meal

Packet formulations can be mixed with a teaspoon of soft food or 5ml liquid

1. food should be at or below room temp

2. entire dose should be taken with 1 hour of mixing

Adverse effects

Cataracts

GI effects N, V,D, ab pain

Hepatotooxicity

CNS effects, HA, dizziness, nueropsyiatric events, suicidia

Increased blood pressure

Ance skin rash

Increase intracranial pressure

Arthralgia (ivacaftor)

Respiratory symptoms (ivacafotr/lumacftor cough dyspnea)

Monitoring

Annual opthathalmoglogic exam

Liver fucntino tests at baseline, Q3 months x 1 year, then annually

CF summary

Cystic fibrosis (CF) is a genetic condition caused by mutations in the

genes encoding CFTR protein expression/functionality.

• This results in impaired chloride transport across epithelial cells, leading to

high chloride concentrations in sweat and dehydration of luminal mucus in

the respiratory and gastrointestinal tracts.

Patients with CF should be managed with a maintenance airway clearance

regimen +/- inhaled antibiotics in an effort to preserve lung function and

reduce the risk of pulmonary exacerbations.

• When exacerbations occur, the intensity of the patient’s airway clearance

regimen should be increased, and they should be initiated on IV antibiotic

therapy in accordance with past and present culture data.

Patients with CF should be placed on a high-fat diet and periodically

assessed from a nutritional standpoint as well as in terms of pancreatic

function.

• Vitamin supplementation and/or pancreatic enzyme replacement therapy

should be initiated when appropriate