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

• 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

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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
Rc Cortisol Release Rate conc/time CCort Cortiso
l 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 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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Quantification of Cortisol Suppression
During Multiple Dosing
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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 A Foral 10 Drug B Foral 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 lt 1 (Falcoz et al.
1996) 200 mg p.o. single dose 1 (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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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 CL 69 L/h Vdss 318
L t1/2 7.8 h
Mackie et al. 1996
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Fluticasone propionatePharmacokinetics 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
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Absorption Profiles of Inhaled Corticosteroids
Cumulative amount absorbed
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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 Bo
chum, Germany