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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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slide1

Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs

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

University of Florida

slide2

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

slide3

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

slide4

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
slide5

PK as a measure of systemic exposure

  • Measurement of plasma concentration profiles
  • Advances from improved analytical sensitivity
  • Route of absorption is irrelevant
  • Safety assessment
slide6

Fluticasone propionate

1 ng/ml

10 pg/ml

slide7

pg/mL

ng/mL

BUD 1000 mg (TH)

FP 500 mg (DK)

ng/mL

ng/mL

FLU 1000 mg (MDI)

TA 2000 mg (MDI)

slide9

PD as a measure of systemic exposure

  • Cortisol
    • 24h Serum Cortisol
    • 24h Urinary Cortisol
    • 8 am Serum Cortisol
    • ACTH Challenge
  • Blood Cells
  • Growth
slide11

17.4% ± 18.7

11.7% ± 19.0

28.0% ± 15.6

35.9% ± 21.5

slide12

Cortisol Baseline

Over one, two and three days

slide13

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

slide14

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

slide19

Lymphocytes

 significant difference from placebo

slide21

Granulocytes

 significant difference from placebo

slide22

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
slide23

PK as a measure of local exposure

  • Direct Measurement
    • Lung Microdialysis
    • Pulmonary Receptor Occupancy
    • g-Scintigraphy
  • Indirect Measurement
    • Pulmonary Absorption Profiles
      • - Charcoal Block
      • - Deconvolution
slide24

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

slide25

Pulmonary Delivery vs. Systemic Bioavailability

Drug AForal = 10%

Drug BForal = 0%

differentiation of pulmonary and gastrointestinal absorption
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
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)

slide28

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)

slide29

Systemic Availability [%]

Absorption Block with CharcoalBudesonide (1 mg)

Thorsson et al. 1994

fluticasone propionate pharmacokinetics after intravenous bolus
Fluticasone propionatePharmacokinetics after intravenous bolus

Linear Pharmacokinetics

CL 69 L/h

Vdss 318 L

t1/2 7.8 h

Mackie et al. 1996

fluticasone propionate pharmacokinetics after inhalation
Fluticasone propionatePharmacokinetics after inhalation

Finh 12-23%

t1/2 14.4 h

Derendorf et al. 1998

Thorsson et al. 1997

Möllmann et al. 1996

slide35

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

?

slide36

PD as a measure of local exposure

  • Therapeutic Efficacy
    • High variability
    • Poor discrimination
  • Surrogate Endpoints
    • No validated markers are available
slide37

Pharmacokinetics

…so much more than just a measure of systemic exposure

slide38

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

slide39

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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