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

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

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

PK as a measure of systemic exposure PD as a measure of systemic exposure PK as a measure of local exposure PD as a measure of local exposure PK/PD Options to Assess BE BE is achieved with equivalent rate and extent of systemic and local exposure

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

1 ng/ml Fluticasone propionate 10 pg/ml

pg/mL ng/mL FP 500  g (DK) TA 2000  g (MDI) FLU 1000  g (MDI) BUD 1000  g (TH)

Nasal Administration

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

Relative Receptor Affinity

17.4% ± % ± % ± % ± 15.6

Cortisol Baseline Over one, two and three days

Cortisol Linear Release Model Cortisol linear release / E max Model R c Cortisol Release Rate [conc/time] C Cort Cortisol Concentration C f Unbound Concentration of Exogenous Steroid k e Elimination Rate Constant of Cortisol E max Maximum Effect (=1) E 50 C f for Half-Maximum Effect

iv poinh Cortisol Suppression Triamcinolone Acetonide 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

Quantification of Cortisol Suppression During Multiple Dosing

Lymphocytes

  significant difference from placebo

Granulocytes

 significant difference from placebo 

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

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

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 Pulmonary Delivery Concepts

Pulmonary Delivery vs. Systemic Bioavailability Drug AF oral = 10% Drug BF oral = 0%

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

Fluticasone Propionate Oral Bioavailability 10 mg BID p.o. for four days< 1% (Falcoz et al. 1996) 200  g p.o. single dose1% (Thorsson et al. 1997)

Absorption Block with Charcoal Budesonide (1 mg) Turbohaler F inh 38%(32% lung + 6% GI) Thorsson et al ___ with charcoal (1mg) ….. without charcoal (1mg) oral with charcoal (4mg) ___ with charcoal (1mg) ….. without charcoal (1mg) oral with charcoal (4mg) MDI F inh 26%(15% lung + 11% GI)

Systemic Availability [%] Thorsson et al Absorption Block with Charcoal Budesonide (1 mg)

Borgström et al Absorption Block with Charcoal Terbutalin

Fluticasone propionate Pharmacokinetics after intravenous bolus Linear Pharmacokinetics CL69 L/h Vd ss 318 L t 1/2 7.8 h Mackie et al. 1996

Fluticasone propionate Pharmacokinetics after inhalation Derendorf et al Thorsson et al Möllmann et al F inh 12-23% t 1/ h

Loo-Riegelman Method

Absorption Profiles of Inhaled Corticosteroids Cumulative amount absorbed

Pharmacokinetics Mean residence time and mean absorption time Mean Residence Time [h] TCAFLUBUDFPBMP ivinh ?

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

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

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

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