Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs

1. Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs Hartmut Derendorf, Ph.D.Günther Hochhaus, Ph.D. University of Florida

2. The Fate of Inhaled Corticosteroids 10 - 40 % Deposited in lung Complete absorption from the lung Lung Systemic Circulation Mouth and pharynx Orally bioavailable fraction Absorption from gut Liver Systemic side effects 60 - 90 % Swallowed (reduced by spacer or mouth rinsing) First-pass inactivation GI tract

3. Inhaled Corticosteroid Therapy • Targeted for high local activity with reduced systemic side effects • Ideal inhaled corticosteroid • Prolonged residence time in the lung • Low oral bioavailability • High systemic clearance • High plasma protein binding } Negligible systemic effect

4. PK/PD Options to Assess BE BE is achieved with equivalent rate and extent of systemic and local exposure • PKas a measure of systemic exposure • PD as a measure of systemicexposure • PKas a measure oflocal exposure • PDas a measure oflocalexposure

5. PK as a measure of systemic exposure • Measurement of plasma concentration profiles • Advances from improved analytical sensitivity • Route of absorption is irrelevant • Safety assessment

6. Fluticasone propionate 1 ng/ml 10 pg/ml

7. pg/mL ng/mL BUD 1000 mg (TH) FP 500 mg (DK) ng/mL ng/mL FLU 1000 mg (MDI) TA 2000 mg (MDI)

8. Nasal Administration

9. PD as a measure of systemic exposure • Cortisol • 24h Serum Cortisol • 24h Urinary Cortisol • 8 am Serum Cortisol • ACTH Challenge • Blood Cells • Growth

10. Relative Receptor Affinity

11. 17.4% ± 18.7 11.7% ± 19.0 28.0% ± 15.6 35.9% ± 21.5

12. Cortisol Baseline Over one, two and three days

13. Cortisol Linear Release Model Cortisol linear release / Emax Model Rc Cortisol Release Rate [conc/time] CCort Cortisol Concentration Cf Unbound Concentration of Exogenous Steroid ke Elimination Rate Constant of Cortisol Emax Maximum Effect (=1) E50 Cf for Half-Maximum Effect

14. Cortisol Suppression Triamcinolone Acetonide iv • intravenous administration (iv) • 2 mg TCA phosphate • oral administration (po) • 5 mg TCA in 100 ml ethanol (4 %) • pulmonary administration (inh) • 2 mg TCA in 20 puffs over 5 minutes po inh

15. During Multiple Dosing Quantification of Cortisol Suppression

18. Lymphocytes

19. Lymphocytes    significant difference from placebo

20. Granulocytes

21. Granulocytes    significant difference from placebo

22. Systemic Exposure • Comparison of two formulations of the same corticosteroid (BE) • Plasma concentration profiles • Comparison of two different corticosteroids • 24h Serum cortisol at steady state

23. PK as a measure of local exposure • Direct Measurement • Lung Microdialysis • Pulmonary Receptor Occupancy • g-Scintigraphy • Indirect Measurement • Pulmonary Absorption Profiles • - Charcoal Block • - Deconvolution

24. Pulmonary Delivery Concepts Only the dissolved and unbound fraction of the drug in the lung is pharmacologically active All of the drug that reaches the cytosolic steroid receptors in the lung will be absorbed systemically ‘Total tissue concentrations’ from biopsies are hybrid numbers and reflect the sum of undissolved, bound and unbound drug

25. Pulmonary Delivery vs. Systemic Bioavailability Drug AForal = 10% Drug BForal = 0%

26. Differentiation of pulmonary and gastrointestinal absorption • Use drugs where GI absorption is negligible • Block GI absorption with charcoal • Utilize early time points where pulmonary absorption is dominant

27. Fluticasone Propionate Oral Bioavailability 10 mg BID p.o. for four days < 1% (Falcoz et al. 1996) 200 mg p.o. single dose 1% (Thorsson et al. 1997)

28. Absorption Block with CharcoalBudesonide (1 mg) ___ with charcoal (1mg) ….. without charcoal (1mg) ----- oral with charcoal (4mg) ___ with charcoal (1mg) ….. without charcoal (1mg) ----- oral with charcoal (4mg) Thorsson et al. 1994 Turbohaler Finh 38%(32% lung + 6% GI) MDI Finh 26%(15% lung + 11% GI)

29. Systemic Availability [%] Absorption Block with CharcoalBudesonide (1 mg) Thorsson et al. 1994

30. Absorption Block with CharcoalTerbutalin Borgström et al. 1990

31. Fluticasone propionatePharmacokinetics after intravenous bolus Linear Pharmacokinetics CL 69 L/h Vdss 318 L t1/2 7.8 h Mackie et al. 1996

32. Fluticasone propionatePharmacokinetics after inhalation Finh 12-23% t1/2 14.4 h Derendorf et al. 1998 Thorsson et al. 1997 Möllmann et al. 1996

33. Loo-Riegelman Method

34. Cumulative amount absorbed Absorption Profiles of Inhaled Corticosteroids

35. Mean Residence Time [h] iv inh 9.6 10 8 5.6 6 4.2 3.8 3.6 4 2.7 1.9 1.9 1.6 2 0 TCA FLU BUD FP BMP Pharmacokinetics Mean residence time and mean absorption time ?

36. PD as a measure of local exposure • Therapeutic Efficacy • High variability • Poor discrimination • Surrogate Endpoints • No validated markers are available

37. Pharmacokinetics …so much more than just a measure of systemic exposure

38. BE of inhaled corticosteroids • In-vitro studies • In-vitro equivalence • In-vivo studies • Equivalent systemic exposure • Equivalent pulmonary absorption profile • - iv study • - inhalation with oral charcoal-block Goalposts need to be defined

39. Acknowledgements Günther Hochhaus, PhD Bernd Meibohm, PhD Shashank Rohatagi, PhD Sriram Krishnaswami Hristina Dimova Department of Pharmaceutics University of Florida Gainesville, FL, U.S.A. Helmut Möllmann, MD Jürgen Barth, MD Melanie Wagner, MD University Hospital Bergmannsheil Bochum, Germany