understanding dermal drug disposition using panellists ...wang-kasting-nitsche potts-guy robinson sc...

Understanding

dermal drug

disposition using

TCAT - a novel

PBPK model

SOT-BMSS

Feb 16th, 2016

Panellists: • Anu Krishnatry

• Valeriu Damian

• Jessica Spires

What is PBPK ?

Wikipedia:

– PBPK modeling is mathematical modeling technique for

predicting the absorption, distribution, metabolism and excretion

(ADME) of synthetic or natural chemical substances in humans and

other animal species.

– PBPK models strive to be mechanistic by mathematically

transcribing anatomical, physiological, physical, and chemical

descriptions of the phenomena involved in the complex ADME

processes.

It is a modeling technique not a single model

2

PBPK is not:

– PBPK is not a single model

Even though a Google image PBPK search reveal only

variations of the same basic model

– PBPK is not just for IV / oral

Detailed oral absorption models (e.g. ACAT/ADAM) coupled

with simple compartmental PK are also PBPK models

– PBPK is not just an alternative to allometry

PBPK can provide tissue concentration predictions, drug

delivery predictions for various dosage routes and much more

– PBPK is not just for small molecules

PBPK is:

– PBPK is a modeling technique

– PBPK is striving to be mechanistic

– PBPK is attempting to separate

physiology from drug related parameters

– PBPK is applicable to all routes of

administration

– PBPK is increasingly accepted by

regulatory

The first documented application of PBPK by FDA was

in 1990s for review and approval tretinoin topical cream

3

Peck, C. C. (2010). Quantitative clinical pharmacology is transforming drug regulation. Journal of Pharmacokinetics and

Pharmacodynamics, 37(6), 617–28.

Is a simple skin absorption model sufficient?

4

Dose

Dermis

Flux

through

skin

Systemic

Diffusion to

systemic

circulation

Systemic

clearance

and

Complex formulation

Complex organ structure

epidermis

dermis

formulation

receptor

capillaries

sweat gland

Site of action

5 Anissimov, Y. G., et al. "Mathematical and pharmacokinetic modelling of epidermal and dermal

transport processes." Advanced Drug Delivery Reviews 65.2 (2013): 169-90.

– The TCAT™ model allows us to predict drug concentration in each skin sublayer

Not all skin is the same

6

4 8 12 16 20

Face

Scalp

Arm

Back

Abdomen

Leg

microns

SC Thickness (µm)

20 50 80 110 140

Face

Scalp

Arm

Back

Abdomen

Leg

microns

VE Thickness (µm)

1100 1400 1700 2000 2300

Face

Scalp

Arm

Back

Abdomen

Leg

microns

DE Thickness (µm)

Face Scalp Arm Back Abdomen Leg0

10

20

30

40Blood Flow Rate

mL

/min

/10

0g

skin

In vitro testing - cumulative amount over 24 h

7

Dissolution, supersaturation and precipitation are very important events

Cu

mu

lative

am

ou

nt

Time (hours)

Solution 0.045%

Solution 1.0%

Solution 0.45%

Compound A:

• Expected behavior

~ 0.5% 2.2% ~ 0.05%

Solution 2.2%

Solution 0.5%

Time (hours)

Solution 0.05%

Compound B:

• Unexpectedly low penetration at high dose

• Precipitation at higher dose

• Dissolution, supersaturation and

precipitation are very important events

FDA Classification of Transdermal Formulations

8

Liquid formulations

clear & homogenous

Emulsion

SOLUTION LOTION SUSPENSION

solid dispersed in a liquid

Semi-solid formulations

Solution of colloidal dispersion with a gelling agent

> 50% water and volatiles

< 50% water and volatiles

Emulsion

GEL CREAM PASTE OINTMENT

> 20-50% dispersed solids < 20-50% dispersed solids

>50% of solids are waxes, PEGs, HCs

< 20% water and volatiles

< 20-50% dispersed solids AND

< 50% of solids are waxes, PEGs, HCs OR

> 20% water and volatiles

Transdermal Formulations

Formulations from a modeling perspective

9

SOLUTION LOTION SUSPENSION

GEL CREAM PASTE OINTMENT

DP

DP

DP

Oil

droplet

Drug

particle

Drug

encapsulated

Disperse phase (DP) Continuous

phase (CP) Liquid

Gel

Semisolid

Ve

hic

le f

or

CP

CP: Liquid vehicle

DP: missing

CP: Liquid vehicle

DP: (oil) Droplet

CP: Liquid vehicle

DP: Particle

CP: Gel vehicle (slower diffusion)

DP: missing

CP: semisolid vehicle (slower diffusion)

DP: droplet


DP: droplet/particle


DP: particle

A “simple” solution formulation

Volatile Fast

Evaporation

(e.g. alcohol)

Non-volatile

(e.g. oils)

• Fast evaporation excipients

disappear quickly (few min)

• They may leave a super saturated

solution

• Huge concentration gradient can

drive drug into skin but can also

cause precipitation

• Water would evaporate in about 15 min

– (perhaps longer in a gel formulation)

• There will be a residual level of non-

volatile oils that would eventually be

absorbed in the skin

Volatile

Slower

Evaporation

(e.g. water)

These stages are modeled explicitly

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800

Perc

en

t o

f in

itia

l w

eig

ht

Time (seconds)

Sample 1

Sample 2

Sample 3

Sample 4

Acetone

100% Ethanol

10

A likely concentration profile in vehicle

Volatile

Slower

Evaporation

(e.g. water)

Drug solubility in non volatile excipient

Drug solubility in slow evaporating excipient

No re-dissolution of

precipitated drug

For many drugs the

absorption window can be

quite small (e.g. 15min)

Fast evaporation

excipient is

completely gone

Drug concentration

in formulation

Precipitation brings concentration

back close to solubility in non-

volatile excipient

Dissolution rate equals

absorption rate

Huge concentration increase

as the slow evaporating

excipient is almost vanished.

time

Co

nc

en

tra

tio

n in

Ve

hic

le

Transdermal Drug Disposition: Key processes

12

Absorption

Release/ Dissolution

Evaporation

Partitioning Binding

Metabolism Binding

Systemic Uptake

Veh

icle

St

ratu

m

corn

eum

V

iab

le

ep

ide

rmis

D

erm

is

Thanks to Siladitya Ray Chaudhuri and Simulations Plus

Binding

Precipitation / Redissolution

Surface area

of skin

Surface area

of hair

Surface area

of follicles

Modeling dermal formulations

13

vCP

Evaporation

Drug and vCP

absorption

into SC

Drug, vCP

and vDP

diffusion and

partitioning

Disperse

phase (DP)

Drug

Diffusion

in vCP

Continuous

phase (CP)

Rest of

skin

Hair

Lipid

outside

Hair

core

outside

Sebum Hair lipid Hair core

SC

pe

rm

Stratum Corneum

Viable epidermis

Systemic Dermis

Drug

absorption

Drug

diffusion and

partitioning

Film phase (FP)

Coalesce of disperse

phase

vDP

Evaporation

Drug and vDP

absorption

into SC

Drug Dependent Input Parameters in SC

14

Diffusion and partition

PwSC

MWSC

K

D

log71.0/

0061.03.6)05.0log(

10

10

5.01786.0log6097.0326.1 0001519.010

1115.0

MWPPhcmP MWPpollipSC

Wang-Kasting-Nitsche

Potts-Guy

Robinson

wSC

SC

SCSC

wSC

K

hPD

K

/

/ 1

Surface area

of skin

Surface area

of hair

Surface area

of follicles

vCP

Evaporation

Drug and vCP

absorption

into SC

Drug, vCP

and vDP

diffusion and

partitioning

Disperse

phase (DP)

Drug

Diffusion

in vCP

Continuous

phase (CP)

Rest of

skin

Hair

Lipid

outside

Hair

core

outside


SC

pe

rm

Stratum Cornea

Viable epidermis

SystemicDermis

Drug

absorption

Drug

diffusion and

partitioning

Film phase (FP)


phase

vDP

Evaporation

Drug and vDP

absorption

into SC

Wang, T., Kasting, G. B., & Nitsche, J. M. (2007). A multiphase microscopic diffusion model for stratum corneum

permeability. II. Estimation of physicochemical parameters, and application to a large permeability

database. Journal of Pharmaceutical Sciences, 96(11), 3024–51. doi:10.1002/jps.20883

Drug Dependent Parameters in Epidermis and Dermis

15


Surface area

of skin

Surface area

of hair

Surface area

of follicles

vCP

Evaporation

Drug and vCP

absorption

into SC

Drug, vCP

and vDP

diffusion and

partitioning

Drug

Diffusion

in vCP

Drug

absorption

Drug

diffusion and

partitioning

Disperse

phase (DP)

Continuous

phase (CP)

Rest of

skin

Hair

Lipid

outside

Hair

core

outside

Hair lipid Hair core

SC

pe

rm

Stratum Corneum

Viable epidermis

Systemic

Film phase (FP)


phase

vDP

Evaporation

Drug and vDP

absorption

into SC

Sebum

Dermis

Valiveti

wSBM

SBMSBM

SBM

wSBM

K

PD

MWPsmP

PK

/

/

008.0

28.00047.0log7856.0)/(log

3329.1log4894.0log

Bunge-Cleek

1

log5.015.5/log

/

2

wVE

VE

K

MWscmD

Robinson

SCVE

VE

VEVE

VE

wVE

K

hPD

MWscmP

K

/

/

log5.016.3/log

1

Kretsos

7.0;

log655.015.4/log

/

2

aq

non

aqwVE

VE

fK

MWscmD

wSC

wVESCVE

K

KK

/

//

Viable epidermis and Dermis

Sebum

Systemic absorption rate in Dermis

16


Surface area

of skin

Surface area

of hair

Surface area

of follicles

vCP

Evaporation

Drug and vCP

absorption

into SC

Drug, vCP

and vDP

diffusion and

partitioning

Drug

Diffusion

in vCP

Drug

absorption

Drug

diffusion and

partitioning

Disperse

phase (DP)

Continuous

phase (CP)

Rest of

skin

Hair

Lipid

outside

Hair

core

outside


SC

pe

rm

Stratum Corneum

Viable epidermis

SystemicDermis

Film phase (FP)


phase

vDP

Evaporation

Drug and vDP

absorption

into SC

L

L

s

s

Pe

PeDE

uj

sys

u

LVL

Pe

PeDE

uj

sys

u

s

cms

mL

Vs

cm

gm

sys

u

DE

uj

cmcm

s

cm

capcap

scm

gm

j

e

eCCJ

e

eCCJ

CCSAPVolRate

11

11

,

,

1

,

1

3

33

2

3

UWL

wUWL

mem

UWLmemcap

h

DP

MWPP

PPP

82.237.1log64.1log

111

31

L

tot

PLVL

s

tot

PsVs

PSL

PSL

J

J

23

1

s

L

s

L

s

L

s

L

s

L

Ls

W

W

A

A

W

W

n

n

SP

JPe

SP

JPe

Lslit

LVLL

sslit

sVss

1

1

2

08428.03192.0

4285.019358.1ln16

91

54

3

i

hyd

i

ii

iiii

w

slit

i

islit

iii

slit

i

W

r

DD

xDLWfP

QVolRate

C

k

sys

u

sys

j

~11

sys

free

DE

j

sys

jj CCkSysRate

IBRAHIM

First order

Ibrahim, R., Nitsche, J. M., & Kasting, G. B. (2012). Dermal clearance model for epidermal bioavailability calculations.

Journal of Pharmaceutical Sciences, 101(6), 2094–2108.

0 500 1000 1500 10

-12

10 -11

10 -10

10 -9

10 -8

10 -7

10 -6

10 -5

MW

Permeability cm/sec (logP=2.0)

WKN_fhm1

WKN_fhm2

WKN_phm1

WKN_phm2

PottsGuy

0 500 1000 1500 10

-15

10 -14

10 -13

10 -12

10 -11

10 -10

10 -9

MW

Diff Coeff cm2/sec (logP=2.0)

minutes

days

Permeability and Diffusion in Stratum Corneum

17

As a function of MW

Model 1

Model 2

hours

Wang-Kasting-Nitsche model 1 for partially hydrated skin


Potts&Guy

Wang-Kasting-Nitsche model 1 for fully hydrated skin


Permeability and Diffusion in Stratum Corneum

18

As a function of Kow

10 -5

10 0

10 5

10 10

10 -11

10 -10

10 -9

10 -8

10 -7

10 -6

10 -5

10 -4

10 -3

MW=250, Perm cm/sec

kow 10

-5 10

0 10

5 10

10 10

-14

10 -13

10 -12

10 -11

10 -10

10 -9

10 -8

MW=250, Diff Coeff cm2/sec

kow

minutes

hours

days

10 -5

10 0

10 5

10 10

10 -1

10 0

10 1

10 2

10 3

10 4

10 5

kow

MW=250, KP



Potts&Guy



Partition - skin capacity to absorb drug

19

Assuming no metabolism, no excipient effects, no protein/melanin binding

0 2 4 6 8

10 0

10 1

10 2

10 3

10 4

10 5

logp

KP

tis

su

e/w

ate

r

SCph SCfh VE DE SB All ph All fh

0 2 4 6 8 0

10

20

30

40

50

60

70

80

90

100

logp p

erc

en

t d

rug in e

ach

regio

n o

f skin

Partially hydrated

SC VE DE SB

• Most drugs can partition into sebum (SB) however sebum volume is low

• For small logP Dermis would have the capacity to hold most drug

• Extremely lipophilic compounds would partition preferentially in SC

• Sebum partitioning is most significant for compounds with logP around 5

Permeability in various skin layers

20

Assuming no metabolism, no excipient effects, no protein/melanin binding

All Skin

0 2 4 6 8

100

200

300

400

500

600

700

800

Permeability [cm/s]Low <----- -----> High

-12 -10 -8 -6 -4 -2Stratum Corneum

0 2 4 6 8

200

400

600

800

Viable Epidermis

0 2 4 6 8

200

400

600

800

Dermis

0 2 4 6 8

200

400

600

800

Sebum

0 2 4 6 8

200

400

600

800

logp

MW

• Stratum corneum is the key diffusion barrier for most compounds (not surprising)

• For most compounds of interest Sebum permeability is quite high

• Metabolism, binding and systemic uptake can make the dermis a more significant barrier

Three dimensional finite element skin model

21

Attempting to model the 3D skin complex structure

https://classconnection.s3.amazonaws.com/993/flashcards/253

993/jpg/bloodvessels_large1313943640766.jpg

Dermis

Epidermis

Formulation

Hair

Formulation

Blood

capillaries

Capillaries near root of hair follicle

Sytratum

Corneum

Sebum

thanks Sumeet Thete

Sample simulation

22

3D finite element model (2D axial symmetry)

MW = 250, logP = 5, no vehicle partitioning, high systemic absorption

LogP effect

23

MW = 250, no vehicle partitioning, high systemic absorption

logP = 5

logP = 2 logP = 8

Less

lipophylic

More

lipophylic

Additional Dosage Routes Modules

Making the PBPK dermal model available

Additional Dosage Routes Modules in GastroPlus

24

Input parameters Output

Oral absorption - ACAT model

Ocular Pulmonary Transdermal

PBPK model

PBPK model

In-vitro to Human - Model Based Translation

25

Principle

PBPK model

In vitro

Drug related

Parameter

In-vitro

Protocol

Human

tissue PK

predictions

Which factors to use?

Is it predictive?

Does it translate?

In-vitro to in-vivo

scaling factors

In-vitro

“Physiology”

Use same PBPK model for both in-vitro and in-vivo

Using more fundamental drug parameters (e.g. diffusion, lipid bilayer permeability)

Human

tissue PK

predictions

In-vitro

data

Human

Physiology

Trial

Protocol

Change the in-vitro conditions to be more relevant to

the in-vivo situation

Predictions

not accurate?

Change model to capture more biological processes

and use more fundamental drug parameters

Human

Physiology

Trial

Protocol

Predictions

not accurate?

Scaling

Approach

Model

Based

Translation

“In–vitro” physiology

26

Using PBPK model to simulate in-vitro skin penetration

TCAT model

Select “Human Abdomen” skin physiology

Adjust Dermis thickness to match skin sample thickness (~450 microns)

Remove sebum (set sebum partition to zero)

Set high systemic absorption rate

“PK” parameters

Match central compartment to receptor chamber

No clearance (all compound accumulates in receptor fluid)

Match volume of distribution with receptor output volume

Set Fu plasma close to zero to match the sink conditions

achieved in receptor chamber

Instead of using

in-vitro flux in PBPK

Validate diffusion and partition parameters

using in-vitro data and use them in PBPK

Match volume of distribution with receptor chamber volume

Set Fu plasma to 100% or according to receiving fluid used

Franz

“static” cells

Bronaugh

“flow-through”

cells

TCAT

model

Excipient effects

27

Release/ Dissolution

Evaporation

Precipitation / Redissolution

Partitioning Binding

Metabolism

Systemic Uptake

Veh

icle

St

ratu

m

corn

eum

V

iab

le

ep

ide

rmis

D

erm

is

Shed / Rub/Wash off

Absorption Diffusion

Systemic Uptake

Partitioning

Penetration enhancement

Partitioning

Absorption Diffusion

Metabolism Binding

Excipients

Modified partitioning

DRUG

Penetration of co-solvent with drug in the tissue

28

Slower penetration of drug compared to solvent

Pro

pyle

ne G

lyco

l K

eto

pro

fen

Saar, B. G., Contreras-Rojas, L. R., Xie, X. S.,

& Guy, R. H. (2011). Imaging drug delivery to

skin with stimulated Raman scattering

microscopy. Molecular Pharmaceutics

Complex formulation

Many components

Different functions Used often

High amount

Significant change

in vehicle solubility

Evaporation

can trigger

on precipitation Used often

Low amount

Can change

coalescence and

film formation

in emulsions

Used often

High amount

(Transient)

Increased diffusion

in SC

Used often

High amount

Use hydrated

SC model

Lower evaporation

Slow diffusion

in VH

Used often

High amount

Change solubility

and partition

in VH SC

Used often

High amount

Significant change in

partition in both

vehicle VH and

Stratum Corneum SC

Used sometimes

High amount

Reduce diffusion

in vehicle

Some may affect

partition in VH

Used often

Med amount

Evaporate quickly

Remove from

dosage volume

before modeling

Used often

High amount

Change Vehicle (VH)

Solubility, Partition

and Evaporation

Used often

Low amount

Minimal impact on

penetration

Used often

Low amount

Use hydrated

SC model

Reduce

evaporation rate

Topical Formulation Components

29

How can we represent this in the model

Caprylocaproyl

Polyoxylglycerides

Diethylene Glycol

Monoethyl Ether

Diisopropyl Adipate

Dimethyl sosorbide

Glyceryl

Monostearate II

(Propylene Glycol)

(Transcutol)

Petrolatum

Glycerin (glycerol)

Polyethylene Glycol 400

Propylene Carbonate

Propylene Glycol

Soybean oil

Medium Chain

Triglycerides

Light Mineral Oil

Oleoyl

Macrogolglycerides

Xanthan Gum

Glyceryl Behenate

Hydroxypropyl Cellulose

Microcrystalline Wax

Wax, Beeswax

Mineral Oil

Benzyl Alcohol

Stearyl Alcohol

Phenoxyethanol

Potassium sorbate

Sorbic Acid

Polysorbate 80

Glycerol Monostearate

Sorbitan Oleate

Cyclomethicone

Isopropyl Myristate

Octyldodecanol

Oleic Acid

Stearic Acid

Sodium Citrate

Buffer

Emollient

Emulsifier

Surfactant

Humectant

Lipid vehicle

Thickener

Solubilizer Solvent

Penetration

enhancer

Preservative

Anu Shilpa Krishnatry

Novel Skin PBPK model in Action:

Clindamycin Modeling

Clindamycin Modeling with TCAT Module

– Clindamycin is lincosamide antiobiotic

– Is usually used to treat infections with anaerobic bacteria

– Common topical treatment for acne

– Typical IV administration seems to be as clindamycin phosphate - phosphate is

quickly converted to clindamycin in the plasma

31

J Med Assoc Thai, 89(5):683-689, 2006

//upload.wikimedia.org/wikipedia/commons/f/fa/Clindamycin_skeletal_improved.png

Available Clinical Data

– Dalacin T solution: 5 mg single application

– Duac Gel: 10 mg single application

– Clindagel: 40 mg QD repeat application

– Evoclin foam: 40 mg QD repeat application

Test if TCAT model can predict exposure

differences with different formulations

Gatti et al., Antimicrob Agents Chemother, 37(5): 1137-1143, 1993 – IV infusion: 600mg of clindamycin phosphate over 25 min

– PO capsule: 600mg of clindamycin hydrochloride (with 170 mL of water)

– Healthy males, average age 27 years, average body weight 73 kg

Plaisance et al., Antimicrob Agents Chemother, 33(5): 618-620, 1989 – 600mg of clindamycin phosphate infused over 30 min every 6 h

– 1200mg of clindamycin phosphate was infused over 1h every 12h

– Healthy males, average age 29 years, average body weight 73 kg

What All information needed for the TCAT model ?

33

epidermis

dermis

formulation

receptor

capillaries

sweat gland

What All information needed to build a TCAT model ?

34

• Compound details

• Log P, pKa

• Solubility at various pH, biorelavant media, solvent

• Permeability

• Protein binding and skin tissue binding

• Blood cell association

• Clearance

• Formulation details

• Type (Solution, suspension, gel, ointment..)

• Volatile components

• Volume

• Dose

• Study Details

• Dosing region (face, arms, scalp, back, abdomen, legs)

• Application surface area

• Skin covered/not

• Any Washing step performed

• Any in vitro flux data

Building Clindamycin TCAT model

35

• Compound details

• Log P, pKa

• Solubility at various pH, biorelavant media, solvent

• Permeability

• Protein binding and skin tissue binding

• Blood cell association

• Clearance

• Formulation details

• Type (Solution, suspension, gel, ointment..)

• Volatile components, solvent evaporation rate

• Volume

• Dose

• API solubility in Formulation

• Study Details

• Dosing region (face, arms, scalp, back, abdomen, legs)

• Application surface area and Time

• Skin covered/not

• Any Washing step performed

• Any in vitro flux data

Predicted / Experimental values

were used for model building.

Systemic disposition was calibrated

against plasma concentration-time

profiles after intravenous

administration from literature


• Diffusivity and partition coefficients calculations:

• In Stratum Corneum using Wang-Kasting Nitsche equation

• In Viable epidermis using Krestos equation

• In Sebum calculated according to the equation derived from Valiveti et al., data

• Sublayers (10, Uniform Grid)

36 Wang et al., J Pharm Sci, 95(3), 2006; Krestos et al., J Pharm Sci, 93(11), 2004; Valiveti S, Wesley J and Lu GW, International J of

Pharmaceutics, 346, 2008.


• Optimized only 2 parameters after accounting for all compound, formulation

and study specific details: Vehicle /Water partition coefficient and systemic

uptake rate

37


38

PK Characterization using Literature Data

Published Human data available

Gatti et al, Antimicrob Agents Chemother, 37(5): 1137-1143, 1993 • IV infusion: 600mg of clindamycin phosphate over 25 min

• PO capsule: 600mg of clindamycin hydrochloride (with 170 mL of water)

• Healthy males, average age 27 years, average body weight 73 kg

Plaisance et al, Antimicrob Agents Chemother, 33(5): 618-620, 1989 • 600mg of clindamycin phosphate infused over 30 min every 6 h

• 1200mg of clindamycin phosphate was infused over 1h every 12h

• Healthy males, average age 29 years, average body weight 73 kg

Data Captured using Digit It

(Simulations Plus)


39

PK Characterization using Literature Data

Antimicrob Agents Chemother, 37(5), 1993; Antimicrob Agents Chemother, 33(5), 1989

Compartmental PK model fitted to match

observed plasma concentration vs. time profile

after 600 mg IV infusion for 25 mins of

Clindamycin phosphate as in Gatti et al. , 600 mg

and 1200mg repeat IV infusions from Plaisance

et al.

Simulating Systemic Exposures from Different Formulations

– In all cases, clindamycin phosphate is dosed and clindamycin is measured

– Single dose administration

– Duac gel

– Dalacin T solution

– Multiple dose administrations

– Evoclin foam

– Clindagel

Simulating Systemic Exposures from Different Formulations

Simulated Plasma concentration vs. time profile (solid line) and observed plasma concentrations (open

squares with CV% as the bars, N=12)

Understanding exposures in various skin compartments

42

Simulating exposures in various skin compartments

43

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 5 10 15 20 25

Dis

solv

ed

Co

nce

ntr

atio

n (

ug/

ml)

Simulation Time (hour)

Dissolved concenteration in Dermis

Dalacin T SolutionDuac Gel ClindagelEvoclin Foam

0

100

200

300

400

500

600

700

0 5 10 15 20 25

Dis

solv

ed

Co

nce

ntr

atio

n (

ug/

ml)

Simulation Time (hour)

Dissolved concenteration in Sebum

Dalacin T SolutionDuac GelClindagel Evoclin Foam

Simulated concentration of Clindamycin in various

skin compartments (VH: Vehicle, SC: Startum

Corneum; VE: Viable Epidermis and DE: Dermis)

at 0, 1, 4, 8, and 24 hours following application of

Dalacin T Solution

Dissolved concentration of Clindamycin in dermis from

different formulations of Clindamycin

Dissolved concentration of Clindamycin in Sebum from

different formulations of Clindamycin

Dis

so

lve

d c

on

ce

ntr

ati

on

44

Clindamycin gets into sebum ?

• As early as 1 hour after application of CT Gel, clindamycin phosphate was diffusely distributed throughout

the dermis with a clear accumulation of drug in and around the hair follicles, and some accumulation

around the sebaceous glands.

• 4 hours after application of CT Gel, significantly more clindamycin phosphate was distributed diffusely

throughout the dermis with a clear accumulation near hair follicles, and sebaceous glands

Micro-autoradiographs of H3-Clindamycin in mouse skin after 1 hour (left) or 4 hours

(right) of administration. Silver grains identify location of radioactive drug in skin

Micro-autoradiography to visualize the localization of drug substance in the skin of mice

Jon Lenn, Stiefel

Poster at 2010 American Academy of Dermatology

45

Clindamycin gets into sebum ?

Clindamycin levels in various body tissues and fluids, Journal of Clinical Pharmacology, July 1972

Novel Skin PBPK Model in Action: Clindamycin and

Tazarotene Modeling

46

AAPS Annual Meeting, San Diego, 2014

Conclusions

• Clindamycin model was able to appropriately characterize exposure differences

with different formulations including a solution, gels, and foam.

• The TCAT model within GastroPlus is a novel model that will enable scientists

to simulate the exposures from different topical formulations.

• Its applications span from candidate compound and formulation decisions to

maximizing the potential for the right amount of drug to be delivered to the

target tissues in the body.

47

48

• Christopher Ruark, Society of Toxicology

• Richard Lloyd

• Tom Wilde

• Betty Hussey

• Grace Kang

• Sumeet Thete (summer student)

Collaborators:

• Viera Lukacova

• Jessica Spires

• Siladitya Ray Chaudhuri

Acknowledgements

understanding dermal drug disposition using panellists ...wang-kasting-nitsche potts-guy robinson sc...

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