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