# Presentation: 929787

## PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS

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

- SE/Expmed/990601

## Pharmacodynamic Testing

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

- SE/Expmed/990601

## 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?

- SE/Expmed/990601

## 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!***

- SE/Expmed/990601

## 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

- SE/Expmed/990601

## Hargreave et al, Inhaled Glucocorticoids in asthma, 1997, 133

- SE/Expmed/990601

## FEV1

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- -75

- -50

- -25

- 0

- 25

- 50

- 75

*****

******

**Treatment (weeks)**

**Exhaled NO (% change)**

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- -15

- -10

- -5

- 0

- 5

- 10

- 15

- 20

**Treatment (weeks)**

**FEV**

**1**

** ****(% change)**

** **

**FEV****1**

**NO**

- Jatakanon, Kharitonov, Lim and Barnes, Thorax 1999, 54: 108

- SE/Expmed/990601

## Therapeutic Equivalence

- Morning PEF (L/min)

- Baseline

- 0-2

- 2-4

- 4-6

- 6-8

- 8-10

- 10-12

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- Two-week interval

**Therapeutic Equivalence**

## Two doses of Pulmicort Turbuhaler vs Placebo in mild (moderate) asthma

- Placebo

- Budesonide

- 200 μg BID

- Budesonide

- 400 μg BID

- Mean change from baseline

- Morning PEF (L/min)

- Baseline

- 0-2

- 2-4

- 4-6

- 6-8

- 8-10

- 10-12

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- Two-week interval

**Kemp et al, 1994**

## Inhaled Fluticasone Propionate

- 0

- 5

- 10

- 15

- 20

- FP 100

- n=129

- FP 200

- FP 400

- FP 800

- n=132

- n=132

- n=133

- L/min

- 

- PEF

-     BDP 400

**Pedersen B & Dahl R, 1993**

## Inhaled Fluticasone PropionateMean Morning PEFR

**Pedersen B & Dahl R et al, 1993**

- 0

- 100

- 200

- 300

- 400

**FP 100**

- n=129

**BDP**** ****400**

- n=126

**FP 200**

- n=132

**FP 400**

- n=132

**FP 800**

- n=133

- L/min

- p = 0.001

- PEFR

- change 14 L/min

**365**

**370**

**371**

**374**

**379**

**Inhaled Fluticasone Propionate****Mean Morning PEFR**

## The Confidence Interval Approach

- Treatment difference

**No diff****.**

**Predetermined limits**

## Comparison of two CFC pMDI formulations

- FDA Pulmonary-Allergy drugs advisory meeting, 1995

**Comparison of two CFC pMDI formulations**

- SE/Expmed/990601

## Therapeutic Equivalence Inhaled CorticosteroidsRecommendations for pharmacodynamic testing

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

****

**dose**

- 102

- 103

- 

**d/2**

**2d**

- 

- 

*****

- SE/Expmed/990601

## Simulated Trial Outcome

**Simulated Trial Outcome**

***Morning PEF***

***NO***

- 100 pat/group

- 500 pat/group

- 50 pat/group

**0/100**
**succesful**

**21/100**
**succesful**

**35/100**
**succesful**

- SE/Expmed/990601

## Asthma Clinical Research Network (1)

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

## Asthma Clinical Research Network (2)

**Measuring Inhaled Corticosteroid Efficacy (MICE)**
- Estimate efficacy at equivalent biosystemic effects
- BDP pMDI+spacer
- TAA pMDI+spacer
- FLU pMDI +spacer
- BUD TBH
- FP pMDI+spacer
- 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

## 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)

- SE/Expmed/990601

## Acknowledgements

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

- SE/Expmed/990601