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PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS

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

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PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS

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  1. PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS Staffan Edsbäcker, Assoc.Prof. University of Lund and Experimental Medicine, AstraZeneca, Lund SE/Expmed/990601

  2. 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

  3. 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

  4. 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

  5. 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

  6. Hargreave et al, Inhaled Glucocorticoids in asthma, 1997, 133 SE/Expmed/990601

  7. Dose-related Effect of Budesonide on FEV1 and Exhaled NO in Asthma budesonide/placebo budesonide/placebo terbutaline terbutaline + terbutaline + terbutaline terbutaline terbutaline Placebo (n=6) m g (n=9) 100 g (n=7) m 400 Placebo m g 100 g m 400 mg * p<0.05 vs 100 mg ** p<0.01 vs 100 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) SE/Expmed/990601 Jatakanon, Kharitonov, Lim and Barnes, Thorax 1999, 54: 108

  8. 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

  9. 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

  10. Inhaled Fluticasone Propionate D PEF 20 15 BDP 400 L/min 10 5 0 FP 100 FP 400 FP 800 FP 200 n=132 n=133 n=129 n=132 Pedersen B & Dahl R, 1993

  11. Inhaled Fluticasone PropionateMean Morning PEFR p = 0.001 PEFR change14 L/min 400 379 374 371 365 370 300 200 L/min 100 0 FP 200 FP 400 FP 800 FP 100 BDP400 n=132 n=132 n=133 n=129 n=126 Pedersen B & Dahl R et al, 1993

  12. The Confidence Interval Approach No diff. Predetermined limits Treatment difference

  13. Comparison of two CFC pMDI formulations FDA Pulmonary-Allergy drugs advisory meeting, 1995 SE/Expmed/990601

  14. 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 SE/Expmed/990601

  15. 2d 2d 2d ½d ½d ½d Simulated Trial Outcome Morning PEF NO 500 pat/group 50 pat/group 100 pat/group 21/100 succesful 35/100 succesful 0/100 succesful SE/Expmed/990601

  16. 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

  17. 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

  18. 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

  19. Acknowledgements • Per Larsson, PhD, biomathematician, AstraZeneca (Statist. Med. 18, 629-641 (1999)) SE/Expmed/990601

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