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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. 10 - 40 % Deposited in lung. Complete absorption from the lung. Lung. Systemic

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Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs

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Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs

Hartmut Derendorf, Ph.D.Günther Hochhaus, Ph.D.

University of Florida


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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


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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


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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


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PK as a measure of systemic exposure

  • Measurement of plasma concentration profiles

  • Advances from improved analytical sensitivity

  • Route of absorption is irrelevant

  • Safety assessment


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Fluticasone propionate

1 ng/ml

10 pg/ml


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pg/mL

ng/mL

BUD 1000 mg (TH)

FP 500 mg (DK)

ng/mL

ng/mL

FLU 1000 mg (MDI)

TA 2000 mg (MDI)


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Nasal Administration


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PD as a measure of systemic exposure

  • Cortisol

    • 24h Serum Cortisol

    • 24h Urinary Cortisol

    • 8 am Serum Cortisol

    • ACTH Challenge

  • Blood Cells

  • Growth


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Relative Receptor Affinity


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17.4% ± 18.7

11.7% ± 19.0

28.0% ± 15.6

35.9% ± 21.5


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Cortisol Baseline

Over one, two and three days


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Cortisol Linear Release Model

Cortisol linear release / Emax Model

RcCortisol Release Rate [conc/time]

CCortCortisol Concentration

CfUnbound Concentration of Exogenous Steroid

keElimination Rate Constant of Cortisol

EmaxMaximum Effect (=1)

E50Cf for Half-Maximum Effect


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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


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During Multiple Dosing

Quantification of Cortisol Suppression


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Lymphocytes


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Lymphocytes

 significant difference from placebo


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Granulocytes


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Granulocytes

 significant difference from placebo


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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


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PK as a measure of local exposure

  • Direct Measurement

    • Lung Microdialysis

    • Pulmonary Receptor Occupancy

    • g-Scintigraphy

  • Indirect Measurement

    • Pulmonary Absorption Profiles

      • - Charcoal Block

      • - Deconvolution


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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


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Pulmonary Delivery vs. Systemic Bioavailability

Drug AForal = 10%

Drug BForal = 0%


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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


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Fluticasone Propionate

Oral Bioavailability

10 mg BID p.o. for four days< 1%

(Falcoz et al. 1996)

200 mg p.o. single dose1%

(Thorsson et al. 1997)


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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)


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Systemic Availability [%]

Absorption Block with CharcoalBudesonide (1 mg)

Thorsson et al. 1994


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Absorption Block with CharcoalTerbutalin

Borgström et al. 1990


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Fluticasone propionatePharmacokinetics after intravenous bolus

Linear Pharmacokinetics

CL69 L/h

Vdss318 L

t1/27.8 h

Mackie et al. 1996


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Fluticasone propionatePharmacokinetics after inhalation

Finh12-23%

t1/214.4 h

Derendorf et al. 1998

Thorsson et al. 1997

Möllmann et al. 1996


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Loo-Riegelman Method


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Cumulative amount absorbed

Absorption Profiles of Inhaled Corticosteroids


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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

?


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PD as a measure of local exposure

  • Therapeutic Efficacy

    • High variability

    • Poor discrimination

  • Surrogate Endpoints

    • No validated markers are available


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Pharmacokinetics

…so much more than just a measure of systemic exposure


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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


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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


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