PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS

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PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS
CORTICOSTEROIDS

• Staffan Edsbäcker, Assoc.Prof.
• University of Lund and Experimental Medicine,
  AstraZeneca, Lund

SE/Expmed/990601
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Pharmacodynamic Testing

• Proof of concept
• new steroid molecules
• new antiinflammatory agents
• Therapeutic equivalence / comparability
• modified/improved formulation
• generic formulation
• Product comparisons
• marketed formulations

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Proof-of-concept

• Efficacy vs placebo and/or comparator
• choose clinically relevant surrogate with little
  variability in validated model
• Safety vs placebo and/or comparator
• cortisol suppression
• Confounding Factors
• unique kinetics?
• selective mode of action?

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Surrogate markers

• a clinical measurement
• statistically associated with a clinical outcome
• with current knowledge is believed to share a
  causal mechanism with the clinical outcome

Surrogates should be - Specific (lung deposition,
biopsy eosinophiles) - Validated (BHR, sputum
eosinophiles) - Proximal (FEV1, morning PEF), -
Practical (NO, U-LTE4) but none is perfect!
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Models

• Selected patient groups
• disease severity (e.g. steroid dependent)
• lung function (e.g. reversibility, predicted)
• BHR, Sputum eosinophiles, NO etc.
• Allergen challenge
• dual reaction
• late reaction

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Hargreave et al, Inhaled Glucocorticoids in
asthma, 1997, 133
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FEV1
NO

75
20
50
15
25
10
( change)
5
0
Exhaled NO ( change)
0
-25
1
-5
FEV
-50
-10


-75
-15
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Treatment (weeks)
Treatment (weeks)
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Jatakanon, Kharitonov, Lim and Barnes, Thorax
1999, 54 108
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Therapeutic Equivalence
60
50
40
30
Mean change from baseline
Morning PEF (L/min)
20
10
0
Baseline
0-2
2-4
4-6
6-8
8-10
10-12
Two-week interval
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Two doses of Pulmicort Turbuhaler vs Placebo in
mild (moderate) asthma
60
50
Placebo
40
Budesonide
200 µg BID
30
Budesonide
Mean change from baseline
Morning PEF (L/min)
400 µg BID
20
10
0
Baseline
0-2
2-4
4-6
6-8
8-10
10-12
Two-week interval
Kemp et al, 1994
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Inhaled Fluticasone Propionate
D
PEF
20
15
BDP 400
L/min
10
5
0
FP 100
FP 200
FP 400
FP 800
n129
n132
n132
n133
Pedersen B Dahl R, 1993
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Inhaled Fluticasone PropionateMean Morning PEFR
p 0.001
PEFR
change 14 L/min
400
379
365
370
371
374
300
200
L/min
100
0
FP 100
BDP 400
FP 200
FP 400
FP 800
n129
n126
n132
n132
n133
Pedersen B Dahl R et al, 1993
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The Confidence Interval Approach
No diff.
Predetermined limits
Treatment difference
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Comparison of two CFC pMDI formulations
FDA Pulmonary-Allergy drugs advisory meeting, 1995
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Therapeutic Equivalence Inhaled
CorticosteroidsRecommendations for
pharmacodynamic testing

• Patients
• strict inclusion criteria
• Design
• dose scaling
• Endpoint
• composite EOS, NO and BHR score

?

?
?
?
d/2
2d
102
103
dose
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Simulated Trial Outcome
Morning PEF
NO
500 pat/group
50 pat/group
100 pat/group
21/100 succesful
35/100 succesful
0/100 succesful
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Asthma Clinical Research Network (1)

• Dose of Inhaled Corticosteroids with Equisystemic
  Effects (DICE)
• estimate dose response for adrenal suppression
  for
• BDP pMDIspacer
• TAA pMDIspacer
• FLU pMDI spacer
• BUD TBH
• FP pMDI
• FP Diskhaler
• 156 mild/moderate asthmatics incrementing bid
  doses, 1 week/dose, 20 patients/group

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Asthma Clinical Research Network (2)

• Measuring Inhaled Corticosteroid Efficacy (MICE)
• Estimate efficacy at equivalent biosystemic
  effects
• BDP pMDIspacer
• TAA pMDIspacer
• FLU pMDI spacer
• BUD TBH
• FP pMDIspacer
• FP Diskhaler
• Select three doses/steroid (5-10, 25-30 and 50
  suppression)
• 300 Moderate asthmatics 2 wks run-in, 6 wks low
  dose 6 wks high dose, 2 wks prednisone. FEV1
  primary variable.
• Pilot study with two products

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Pharmacodynamic Testing of Inhaled
Corticosteroids - Conclusion

• If carefully designed and executed
• essential part of proof-of-concept
• appropriate for equivalence testing
• valuable for drug product comparisons
• Special care needs to be put on
• selection of patients
• study design
• selection of surrogate marker(s)

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Acknowledgements

• Per Larsson, PhD, biomathematician, AstraZeneca
  (Statist. Med. 18, 629-641 (1999))

SE/Expmed/990601