Current Drug Therapy Issues in Patients with Cystic Fibrosis

1
Current Drug Therapy Issues in Patients with
Cystic Fibrosis

• Robert J. Kuhn, Pharm.D.
• Professor and Vice Chair for Ambulatory Care
• Division of Pharmacy Practice and Science
• Colleges of Pharmacy and Medicine
• University of Kentucky

2
Cumulative Therapies for CF Lung Disease
Volume Replenishment INS 37217 Moli 1901 Na
Channel Blockers Reduce Mucus Burden Mucolytics L
OMUCIN EGF-R Antagonists Anaerobic Ps. a.
Drugs Macrolides Protegrins (?) Novel Reduce
Inflammation Pulmozyme Macrolides LTB4
Antagonists Anti-Inflammatories
3
rhDNase I- Pulmozyme

• Breaks down extracellular DNA in mucus secondary
  to chronic inflammation and tissue destruction
• Aerosolized Dosage form 2.5mg inhalation daily
  for chronic therapy
• Acts as a mucolytic
• Side Effect Profile Very benign
• Treatment Cost 1000.00/month

4
Gastrointestinal Involvement

• Fat malabsorption- lipase deficiency
• Vitamin replacement therapy- Vitamins ADEK oral
  and liquid preparations
• ADEK vitamin supplementation
• Steatorrhea and dosing of enzymes- Watch
  escalation of enzyme dosing
• 2500 units/kg/meal of lipase- risk of DIOS
• Distal Intestinal Obstruction Syndrome

5
Gastrointestinal Involvement

• CF Colonopathy
• Distal Intestinal Obstruction Syndrome
• Treatment 60-100ml/kg GoLytely or balanced
  electrolyte solution
• May require surgical intervention- may be a
  problem of enzyme non-compliance
• Dosing of enzymes with meals and snacks

6
Gastrointestinal Involvement

• Acid blockers, PPI and other drugs
• Hypersecretory pH in portion of CF patients
• Push enzyme dose to 2500 units, then add pH
  altering drug- H-2 or PPI preferred
• Check for fecal fat component to assess dosing
• Weight gain is the most important outcome

7
Reports of Treatment Failures

• Among products- although labeled standard to
  lipase , many patients respond differently to
  products marketed before 1995
• Pancreatic enzyme therapy substitution has lead
  to treatment failures- NEJM 19973361283-89.

8
Todays Situation- Generic Substitution of
Pancreatic Enzymes

• Generic Substitution despite
• Different amount of protease, lipase and amylase
• Different microencapsulated and microtablet
  technology used
• Know intrapatient variability
• Data supporting new productsIllegal Action- as
  viewed by FDA
• Growing List of Treatment Failures

9
Resistance to gastric juice referred to of
actual activity
10
Cholestasis and Liver Disease in CF- A Emerging
Problems

• Longer life expectancy- more clinically apparent
  liver disease
• 3-4X in Liver Panel
• Start ursodiol (UDCA) 20mg/kg/dose bid- maximum
  dose 600mg BID
• Watch LFTs for improvement
• Recheck in 2-3 months

11
CF Pathogens

• Staphylococcus aureus
• Streptococcus pneumoniae
• Pseudomonas aeruginosa - mucoid and non-mucoid
  strains
• Burkholderia cepacia
• Stenotrophomonas multophilia
• Alcaligenes xylosoxidans
• Haemophilus influenzae

12
The Presence of Mucoid P. aeruginosa in Cystic
Fibrosis A Well Characterized Predictor of Poor
Survival
No P. aeruginosa (n12)
Non-mucoid P. aeruginosa in sputum (n19)
Mucoid P. aeruginosa in sputum (n50)
Henry RL, et al. Pediatric Pulmonology.
199212158-161
13
Treatment of Acute Exacerbation

• 10-14 Days of therapy with dual AP therapy is
  gold standard
• Aggressive management with aminoglycosides - peak
  10-14mcg/ml - trough concentration lt 1mcg.ml
• Once a day aminoglycosides/Twice a day
• Beta-lactam continuous dosing

14
Aminoglycosides- 2003 revisited

• Worked for years- synergy and q8H
• Increased dosing requirements
• Most CF patients clear the majority of the drug
  with each dose
• Once a day therapy- twice a day
• Post antibiotic Effect- Is there one in CF?
• Toxicity and monitoring-issues of testing and
  cumulative dose

15
Drugs and Doses for Acute Exacerbations

• Tobramycin 2.5-3mg/kg/dose q8h
• Amikacin 7.5-10mg/kg/dose q8h
• Ciprofloxacin IV 10mg/kg/dose q8h
• Ciprofloxacin (oral) 40-50mg/kg/day Q8-12h
• Ceftazidime 50-70mg/kg/dose q8h
• Cefepime 50mg/kg/dose q8h
• Aztreonam 50-70mg/kg/dose q8h
• Piperacillin 300-500mg/kg/day q4-6h

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Drugs and Doses for Acute Exacerbations-II

• Meropenem 50-70mg/kg/dose q8h
• Imipenem 50-70mg/kg/dose q6h
• Chloramphenicol 50-100mg/kg/day q6h

17
Once a day / Twice a day

• Higher concentration in serum higher
  concentration in sputum
• Decreased toxicity
• 2-6 hour post antibiotic effect
• Not true in CF
• My experience - more data needed
• Once a day is indeed safe but long term efficacy
  MAY be a problem

18
Once a day principle

• For patients with rapid clearance- 2hours or
  less, less than 21 years of age and with no
  underlying CFRD or renal disease (with
  progressive symptoms)
• Take conventional Dose of once a day tobramycin-
  7mg/kg and administer two times a day. Draw
  levels after second dose- 3 hours post and 10
  hours post. May have to increase levels
• Goal of Therapy- 10 hour post level below the
  MIC--1mcg/ml and redose 2 hours later

19
Remember

• No clinical trial results available to this as
  yet
• Based on principles of drug use
• Older patients or those with longer half lives
  should not be on this therapy unless it is
  modified based on pharmacokinetics
• Hearing test- follow up

20
Colistin and Ciprofloxacin

• Treated patient when PA first appears in sputum
  regardless of clinical symptoms
• Dose Inhaled Colistin 75mg (1MU BID) with
  ciprofloxacin 20mg/kg/day
• Delayed time to first exacerbation or
  hospitalization
• No resistance or fungal overgrowth noted

21
Aerosol Delivery

• Advantages
• Less systemic toxicity
• Delivery to site of action
• Higher concentrations available in the lung
• Disadvantages
• Time and Effort
• Delivery Device constraints

22
Important Concepts

• Particle Size-Mass Median Aerodynamic
  Diameter-0.5-5microns
• Respiratory Fraction- Amount of Drug Delivered by
  Device
• Types of Nebulizer- Jet vs. Ultrasonic
• Various Models of Jet Nebulizers--it does make a
  difference.

23
Aerosol Properties

• Isotonic
• Sterile and Pyrogen Free
• Unit of Use
• Tasteless or Pleasant Tasting
• No preservatives or toxic materials
• Solutions which can be easily nebulized
• Good Chemical Stability

24
Antimicrobials that have been Aerosolized

• Ticarcillin- hypertonic and irritating to BSM
• Tobramycin- Bad taste and hypotonic, contains
  phenol
• Amphotercin B- NC with NS and Suspension (dose
  5-10mg BID in Sterile Water)
• Gentamicin- preservatives with phenol
• Colistimethane- foams badly
• Ceftazidime- hypertonic and irritating to BSM

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Aerosolized Antibiotics in CFFeature Comparison
Cost/g ()
Solution Sterility
Solution Stability
Excipients
Antibiotic
Colistimethate Powder Unknown Unknown Formaldehyd
e, 272.17 bisulfites Gentamicin 40 mg/mL
solution 2 y Yes Methylparabens,
37.36 propylparabens, EDTA Tobramycin 40
mg/mL Nebcin 2 y Yes Phenol, bisulfites, 101.10
solution EDTA Preservative-free Unknown Unknow
n None 247.50 Nebcin powder Preservative-free
2 y Yes None 149.28 TOBI solution
Average wholesale price, 2000 Red Book Annual.
26
Aminoglycosides - Binding

• Primary binding in patients with CF
• Glycoproteins----90
• Divalent ions 5
• DNA 2
• Principle- competitive binding- so total drug
  concentration must be many times the MIC to allow
  free drug to work

27
In Vitro Inhibition of Tobramycin Activity by
Sputum
Sputum
8
7
6
Log10 CFU/mL
Sputum Tobramycin (10X MIC)
5
4

Sputum Tobramycin (25X MIC)
3
0
1
2
3
4
Time (hours)
Mendelman PM, et al. Am Rev Respir Dis
1985132761-765
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Differential Effects of TOBI on FEV1 By Age
Group
Age Group 13 - lt 18
Age Group 6 - lt 13
On Drug
On Drug
On Drug
On Drug
On Drug
On Drug
28
24
20
TOBI
16
12
Relative Change in ( SEM) FEV1 Predicted
8
4
0
Placebo
-4
-8
-12
0
4
8
12
16
20
24
Week
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New Devices and Technology

• Trials underway with new nebulizer- handheld with
  delivery time of 4-5 minutes
• Extremely compact and lightweight
• No electrical source needed
• Improved compliance and perhaps outcomes
• Dedicated Disposable cassettes or units

30
Changes in Drug Susceptibility with Standard CF
Antibiotic Therapies
100
³ 16 µg/mLIV TobramycinThomassen et al., 1987
³ 16 µg/mLIV TobramycinMcLaughlin et al., 1983
³ 2 µg/mLOral CiprofloxacinShalit et al., 1987
³ 16 µg/mL Inhaled Tobramycin This study
90
80
70
14 days
of Patients with Resistant Isolates
60
14 days
24 months
50
Baseline
18 months
12 months
Baseline
40
6 months
10 days
30
Baseline
Baseline
20
10
Highest MIC Isolate used to Represent each
Patient
0
31
Safety of Fluoroquinolones

• The real question in pediatric patients with
  Cystic Fibrosis is dose and prudent use
• Dosing issues critical
• Toxicity does not appear to be a major problem
• Resistance can be!

32
Inflammation in CF

• Exuberant but ineffective response by
  neutrophils, IgG, macrophages and complement
• Massive influx of neutrophils into the airway
  which release
• Elastase, proteinase, collagenase
• Oxidants and IL-8
• Cytokine imbalance

33
Inflammation in CF

• Neutrophil predominates (BAL fluid)

• IL-8 principal inflammatory cytokine, IL-10
  levels reduced in BECs

Bonfield TL, et al. J All Clin Immunol
199910472-8.
Henig NR et al. Thorax 200156306-11
34
Ibuprofen

• Double-blind trial in 85 patients over 4 years
  demonstrated a slower annual rate of decline in
  lung function in patients treated with high dose
  ibuprofen.
• Ibuprofen
• FEV1 decline -2.17 (S.E0.57) / year
• Placebo
• FEV1 decline -3.60 (S.E0.55) / year

35
Macrolides

• Anti-inflammatory Effects
• Decrease neutrophil oxidant production
• Decrease macrophage production of the
  pro-inflammatory cytokines IL-8, IL-6, TNF-alpha,
  and IL-1 (alpha and beta) BAD CYTOKINES
• Increase macrophage production of IL-10, a
  cytoprotective cytokine GOOD CYTOKINE

36
Macrolides

• Anti-Pseudomonal Effects
• Decrease pili formation (the hooks that allow
  Pseudomonas to stick to the lining of the lung)
• Decrease exotoxin production (elastase, protease,
  lecthinase, DNase, coagulase) - substances that
  irritate and damage the lung
• Inhibit formation of flagella
• Inhibit production of alginate, its protective
  coating

37
Study Design Macrolide Trial
-14
28
0
84
168
196
Day
Treatment Phase
F/U
Visit
3
1
2
4
5
6
Treatment Phase gt 40 kg 500 mg or Placebo on
MWF lt 40 kg 250 mg or Placebo on MWF
Provisions for step-down regimen
38
Number of Participants in the Trial

39
Relative Change in FEV1 Predicted
Day 168 Treatment Effect 6.21 (p0.001)
Day 168 ? 4.44
Azithromycin
Placebo
Day 168 ? -1.77
Study Day
40
Proportion of Participants Exacerbation Free
40 Reduction in Exacerbations (p0.01)
Study Day
41
Treatment Emergent Changes in Microbiology
p0.06 p0.01
42
Paradigm Shift- First Acquistion

• When to treat
• What to use
• How long to use it
• How it this therapy affect the rate of decline
  and other clinical measures
• Treatment Burden Issues

43
First PA Culture

• Window of Opportunity
• No detectable antibody production
• Non- mucoid strains
• Intermittent detection
• Eradication versus plateau effect

44
Previous Work on Eradication

• 1985- Littlewood- 7 patient OL Coly 2MU BID for
  3-13 months of therapy
• Decrease PC from 42 to 6
• Valerius -1991-Randomized OL COLY plus oral
  Cipro-20mg/kg/day-3 weeks up to 3 months-duration
  27months
• Chronic PA 14 vs 58 -Control
• Fewer PA isolates 23 vs 41

45
Aerosol Initiation Therapy Studies

• Ratjen-2001-80mg BID x 12 months-OL
• 14/15 patients- PA and AB negative
• At 2 years, 9 pts AB negative, NO decrease in
  PFTs
• Treatment burden issues- my opinion
• Dosing of the 1980s

46
Combo Therapy-Tune Up and Maintainence

• Munck et al-2001- 2 Drug AP IV therapy for three
  weeks then 2 months of Coly
• OL-Non controlled-19patients-pts with fewer than
  2 precipitin AB
• 100 eradication at one month post Txt
• Recolonized 3-25 months- Median PA free 8 /- 5.7
  months
• 14/19 patient developed NS by genotyping

47
Combo Therapy-Tune Up and Maintainence

• Wainwright-2002- IV tob and timentin or CTZ x 2
  weeks, then TOBI 300mg BID plus CIPRO 20mg/kg/day
• Multicenter, Randomized (infants less than 6
  months old) to test PA detection by BAL or
  clinical presentation
• 13 subjects negative after treatment15

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Paradigm Shift- First Acquistion

• When to treat? First PA culture
• What to use? Inhaled x 1month to 1 year /-
  CIPRO /- IV antibiotics x 2-3 weeks
• How long to use it? See above
• How it this therapy affect the rate of decline
  and other clinical measures? Decreased rate of
  PA isolation maybe effect on preserving lung
  function
• Treatment Burden Issues. 3 weeks inhaled to 1
  year

49
Resistance with Macrolides and Fluroquinolones

• National Trial showed no evidence of increase in
  MRSA and SA infections in treated group
• 2 Year follow up trial in 104 patients with pilot
  data confirms this observations- Rizzo S, Anstead
  M et al. Pediatric Pulm 2002 Suppl 192002
  Abstract 321
• 2 Year Follow up with Fluroquinolones
  demonstrated a 2.6 fold increase in MRSA with
  fluroquinolone exposure. Whitby, D, Rizzo S et
  al 11th Annual PPAG Meeting Platform
  Presentation St. Petersburg. Fl Oct 2002
• Careful use of FQ still warranted with high dose
  short term strategy
• Macrolide Data promising for continued use at
  this time

50
Conclusions

• Infection and inflammation are severe and
  continuous in CF.
• Aggressive antibiotic and anti-inflammatory
  therapy improve survival in cystic fibrosis and
  must start early.
• Establishing safer, more effective
  anti-inflammatory agents is a key step in
  improving quality of life and survival for CF
  patients.