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. 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

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

University of Florida


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The Fate of Inhaled Corticosteroids Exposure of Locally Acting Drugs

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 Exposure of Locally Acting Drugs

  • 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 Exposure of Locally Acting Drugs

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 Exposure of Locally Acting Drugs

  • Measurement of plasma concentration profiles

  • Advances from improved analytical sensitivity

  • Route of absorption is irrelevant

  • Safety assessment


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Fluticasone propionate Exposure of Locally Acting Drugs

1 ng/ml

10 pg/ml


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pg/mL Exposure of Locally Acting Drugs

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 Exposure of Locally Acting Drugs


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PD as a measure of systemic exposure Exposure of Locally Acting Drugs

  • Cortisol

    • 24h Serum Cortisol

    • 24h Urinary Cortisol

    • 8 am Serum Cortisol

    • ACTH Challenge

  • Blood Cells

  • Growth


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Relative Receptor Affinity Exposure of Locally Acting Drugs


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17.4% ± 18.7 Exposure of Locally Acting Drugs

11.7% ± 19.0

28.0% ± 15.6

35.9% ± 21.5


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Cortisol Baseline Exposure of Locally Acting Drugs

Over one, two and three days


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Cortisol Linear Release Model Exposure of Locally Acting Drugs

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


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Cortisol Suppression Exposure of Locally Acting Drugs

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 Exposure of Locally Acting Drugs

Quantification of Cortisol Suppression


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Lymphocytes Exposure of Locally Acting Drugs


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Lymphocytes Exposure of Locally Acting Drugs

 significant difference from placebo


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Granulocytes Exposure of Locally Acting Drugs


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Granulocytes Exposure of Locally Acting Drugs

 significant difference from placebo


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Systemic Exposure Exposure of Locally Acting Drugs

  • 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 Exposure of Locally Acting Drugs

  • Direct Measurement

    • Lung Microdialysis

    • Pulmonary Receptor Occupancy

    • g-Scintigraphy

  • Indirect Measurement

    • Pulmonary Absorption Profiles

      • - Charcoal Block

      • - Deconvolution


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Pulmonary Delivery Concepts Exposure of Locally Acting Drugs

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. Exposure of Locally Acting Drugs Systemic Bioavailability

Drug AForal = 10%

Drug BForal = 0%


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Differentiation of pulmonary and gastrointestinal absorption Exposure of Locally Acting Drugs

  • 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 Exposure of Locally Acting Drugs

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)


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Absorption Block with Charcoal Exposure of Locally Acting DrugsBudesonide (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 [%] Exposure of Locally Acting Drugs

Absorption Block with CharcoalBudesonide (1 mg)

Thorsson et al. 1994


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Absorption Block with Charcoal Exposure of Locally Acting DrugsTerbutalin

Borgström et al. 1990


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Fluticasone propionate Exposure of Locally Acting DrugsPharmacokinetics after intravenous bolus

Linear Pharmacokinetics

CL 69 L/h

Vdss 318 L

t1/2 7.8 h

Mackie et al. 1996


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Fluticasone propionate Exposure of Locally Acting DrugsPharmacokinetics after inhalation

Finh 12-23%

t1/2 14.4 h

Derendorf et al. 1998

Thorsson et al. 1997

Möllmann et al. 1996


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Loo-Riegelman Method Exposure of Locally Acting Drugs


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Cumulative amount absorbed Exposure of Locally Acting Drugs

Absorption Profiles of Inhaled Corticosteroids


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Mean Residence Time [h] Exposure of Locally Acting Drugs

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 Exposure of Locally Acting Drugs

  • Therapeutic Efficacy

    • High variability

    • Poor discrimination

  • Surrogate Endpoints

    • No validated markers are available


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Pharmacokinetics Exposure of Locally Acting Drugs

…so much more than just a measure of systemic exposure


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BE of inhaled corticosteroids Exposure of Locally Acting Drugs

  • 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 Exposure of Locally Acting Drugs

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