understanding dermal drug disposition using panellists ...wang-kasting-nitsche potts-guy robinson sc...
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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
CP: semisolid vehicle (slower diffusion)
DP: droplet/particle
CP: semisolid vehicle (slower diffusion)
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
Sebum Hair lipid Hair core
SC
pe
rm
Stratum Cornea
Viable epidermis
SystemicDermis
Drug
absorption
Drug
diffusion and
partitioning
Film phase (FP)
Coalesce of disperse
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
Diffusion and partition
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)
Coalesce of disperse
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
Diffusion and partition
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
Sebum Hair lipid Hair core
SC
pe
rm
Stratum Corneum
Viable epidermis
SystemicDermis
Film phase (FP)
Coalesce of disperse
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
Wang-Kasting-Nitsche model 2 for partially hydrated skin
Potts&Guy
Wang-Kasting-Nitsche model 1 for fully hydrated skin
Wang-Kasting-Nitsche model 2 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
Wang-Kasting-Nitsche model 1 for partially hydrated skin
Wang-Kasting-Nitsche model 2 for partially hydrated skin
Potts&Guy
Wang-Kasting-Nitsche model 1 for fully hydrated skin
Wang-Kasting-Nitsche model 2 for fully hydrated skin
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
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
Building Clindamycin TCAT model
• 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.
Building Clindamycin TCAT model
• Optimized only 2 parameters after accounting for all compound, formulation
and study specific details: Vehicle /Water partition coefficient and systemic
uptake rate
37
Building Clindamycin TCAT model
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)
Building Clindamycin TCAT model
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