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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
60 - 90 % Swallowed(reduced by spaceror mouth rinsing)
Mouth and pharynx
GI tract
10 - 40 % Deposited in lung
Lung
Complete absorptionfrom the lung
SystemicCirculation
Systemicside effects
Liver
Orally bioavailablefraction
Absorptionfrom gut
First-passinactivation
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}
•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
CC8
0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80Time0
100
%
0
100
%
FP-MAR1-3 Sm (Mn, 1x2) MRM of 2 Channels AP- 503.27 > 380.00
2.39e41.03
FP-MAR1-3 MRM of 2 Channels AP- 500.20 > 380.00
9631.05
0.900.26 0.53 0.723.502.702.04
1.951.561.521.38 1.87 2.472.35
2.12 2.553.343.09
2.76 3.01 3.28 3.833.54 3.96
Internal Standard
10 pg / ml
1 ng/ml
Fluticasone propionate
10 pg/ml
0 4 8 12 16 20 24
0
30
60
90
120
150
Time (h)
FP
(pg
/ml)
Budesonide 1000 µg
0 2 4 6 8 10 12 14 16
Time (h)
0.0
0.3
0.6
0.9
1.2
1.5
Bud
eson
ide
(ng/
ml)
Time (h)
Concentration (ng/m
l)
22 26 30 34 38 42 46
0
1
2
3
0 4 8 12 16 20
0
2
4
6
8
10
12
FLU
Con
cent
ratio
n (n
g/m
l)
0 2 4 6 8 10 12
Time (h)
pg
/mL
ng
/mL
ng
/mL
ng
/mL
FP 500 g (DK)
TA 2000 g (MDI) FLU 1000 g (MDI)
BUD 1000 g (TH)
Nasal Administration
0 2 4 6 8 10 120.00
0.01
0.02
0.03
0.04
0.05
200ug FP 400ug FP
Nasal Administration of FPC
on
c. (
ng
/ml)
Time (h)
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
0
200
400
600
800
1000
1200
1400
1600
1800
HC MP DEX FLU TCA BUD BMP FP
0 6 12 18 240
50
100
150
200
250
300
Budesonide 1000 ug/Placebo
BUD 1000 ug Placebo
Co
rtis
ol (
ng
/ml)
Time (h)
96 102 108 114 1200
50
100
150
200
250
300
Budesonide 1000 ug/Placebo
BUD 1000 ug Placebo
Co
rtis
ol (
ng
/ml)
Time (h)
17.4% ± 18.7
35.9% ± 21.5
0 6 12 18 240
50
100
150
200
250
300
FP 500 ug/Placebo
FP 500 ug Placebo
Co
rtis
ol (
ng
/ml)
Time (h)
11.7% ± 19.0
96 102 108 114 1200
50
100
150
200
250
300
FP 500 ug/Placebo
FP 500 ug Placebo
Co
rtis
ol (
ng
/ml)
Time (h)
28.0% ± 15.6
Cortisol Baseline
Over one, two and three days
Cortisol Linear Release Model
dC
dtR
E C
E Ck CCort
C
f
fe Cort
1
50
max
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
iv
po inh
Cortisol SuppressionTriamcinolone 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
32 40 48 56 64 72 80
Time (h)
0
50
100
150
Cortiso
l conce
ntra
tion (n
g/m
l)
4 pm 4 pm 4 pm 12 am 12 am8 am 8 am
AUCSupp
Co
rtis
ol C
once
ntr
atio
n (
ng
/ml)
During Multiple Dosing
0%
20%
40%
60%
80%
100%
0% 20% 40% 60% 80% 100%
Measured CCS
Pre
dic
ted
CC
S
FP BUD TA FLU
Lymphocytes
1600
2000
2400
2800
3200
Placebo BUD400 BUD1000 FP200 FP500
AU
C
day 1
day 5
Lymphocytes
significant difference from placebo
Granulocytes
96 102 108 114 12050
75
100
125
150
Budesonide 1000 ug/Placebo
BUD 1000 ug Placebo
Gra
nu
locyte
s (%
of B
aselin
e)
Time (h)96 102 108 114 120
50
75
100
125
150
Budesonide 400 ug/Placebo
BUD 400 ug Placebo
Gra
nu
locyte
s (%
of B
aselin
e)
Time (h)
0 6 12 18 2450
75
100
125
150
Budesonide 400 ug/Placebo
BUD 400 ug Placebo
Gra
nu
locyte
s (%
of B
aselin
e)
Time (h)
0 6 12 18 2450
75
100
125
150
Budesonide 1000 ug/Placebo
BUD 1000 ug Placebo
Gra
nu
locyte
s (%
of B
aselin
e)
Time (h)
Granulocytes
significant difference from placebo
1600
2000
2400
2800
3200
3600
Placebo BUD400 BUD1000 FP200 FP500
AU
C
day 1
day 5
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 A Foral = 10%
Drug B Foral = 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 dose 1%(Thorsson et al. 1997)
Absorption Block with CharcoalBudesonide (1 mg)
TurbohalerFinh 38%(32% lung + 6% GI)
Thorsson et al. 1994
___ with charcoal (1mg)
….. without charcoal (1mg)
----- oral with charcoal (4mg)
___ with charcoal (1mg)
….. without charcoal (1mg)
----- oral with charcoal (4mg)
MDIFinh 26%(15% lung + 11% GI)
0
10
20
30
40
Turbohaler MDI
GI
lung
Sys
tem
ic A
vaila
bili
ty [
%]
Thorsson et al. 1994
Absorption Block with CharcoalBudesonide (1 mg)
0
2
4
6
8
10
% oral bioavailability
without charcoal with charcoalBorgström et al. 1990
Absorption Block with CharcoalTerbutalin
Fluticasone propionatePharmacokinetics after intravenous bolus
Linear Pharmacokinetics
CL 69 L/h
Vdss 318 L
t1/2 7.8 h
Mackie et al. 1996
Fluticasone propionatePharmacokinetics after inhalation
Derendorf et al. 1998Thorsson et al. 1997Möllmann et al. 1996
Finh 12-23%
t1/2 14.4 h
Loo-Riegelman Method
AUCkVc
XpAUCkC
A
At
ttt
10
10
2
1
212
21
0120 2121
tt
Ck
ek
Cke
Vc
Xp
Vc
Xp tktkt
Absorption Profiles of Inhaled CorticosteroidsCumulative amount absorbed
0 2 4 6 8 10 12
Time (h)
0
20
40
60
80
100
Cum
ula
tive a
mount a
bso
rbed (%
)
BUD vs TIME
FLU vs TIME
FP vs TIME
TCA vs TIME
FLU
FP
TCA
BUD
PharmacokineticsMean residence time and mean absorption time
Mean Residence Time [h]
2.71.9
3.64.2
1.6
5.6
1.9
3.8
9.6
0
2
4
6
8
10
TCA FLU BUD FP BMP
iv inh
?
Mean Absorption Time [h]
2.9
0.05 0.2
4.9
0
1
2
3
4
5
TCA FLU BUD FP
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 PharmaceuticsUniversity of Florida
Gainesville, FL, U.S.A.
Helmut Möllmann, MD
Jürgen Barth, MD
Melanie Wagner, MD
University HospitalBergmannsheil
Bochum, Germany