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Assessing the BA and BE of
Topical Dermatologic Drug Products
with Multiple Surrogate Methods
Thomas J. Franz
(Partial) Hierarchy of Surrogate Tests
Veh SC Epi Dermis
IVRT
Tape Stripping
TEWL / Exfol.
Microdialysis
Skin Irritation
IVPT (Blood)
Vasoconstriction
In Vitro Permeation Test
Diffusion Cell
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Nizoral
10% PG; 10% IPM
15% PG; 3.3% IPM
19% PG; 4.2% IPM
Ketoconazole
In Vitro Percutaneous Absorption
Nizoral
Lemmon # 083
Lemmon # 074
Lemmon # 080
µg
/cm
2/h
r
Time (hr)
Nizoral
Generic #1
Generic #2
Generic #3
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
Nizoral
16% PG; 4.2% IPM
16% PG; 8% IPM
18% PG; 8% IPM
Ketoconazole
In Vitro Percutaneous Absorption
Nizoral
Lemmon's 0676-091A
Lemmon's 0676-091B
Lemmon's 0676-091C
µg
/cm
2/h
r
Time (hr)
Nizoral
Generic #4
Generic #5
Generic #6
1 2 3 4 5 61
10
100
Hytone 1%
Cortizone 1%
Hydrocortisone
Tape Strip Study
2 Hr Exposure, No Occlusion
(*2)
Am
ou
nt
Re
co
ve
red
(µ
g)
Tape Strip Set (5 tapes/set)
Topical BE: Tape Stripping (Mean ± SEM)
Method
• 6 subjects
• Vent. Forearm
• A = 2 cm x 5 cm
• Dose = 1.9 mg/cm2
• 1̋ Transpore tape,
22 strips
pooled (2, 5, 5, 5, 5)
• Extract in methanol
• Assay by HPLC
1 2 3 4 5 61
10
100
Hydrocortisone
Tape Strip Study
8 Hr Exposure, No Occlusion
(*2)
Hytone 1%
Cortizone 1%
Am
ou
nt
Re
co
ve
red
(µ
g)
Tape Strip Set (5 strips/set)
Topical BE: Tape Stripping (Mean ± SEM)
2 hr NOC 8 hr NOC 8 hr OC 16 hr OC0
1
2
3
4
5
6
7
Hydrocortisone
Tape Stripping Study
Am
ou
nt
Re
cove
red
(µ
g)
Exposure Conditions
Tape Strips # 18-22 Only
Hytone 1%
Cortizone 1%
Topical BE: Tape Stripping (Mean ± SEM)
Lehman 07Sept04
In Vitro Cadaver Skin Assay
0
50
100
150
200
250
300
Eldoquin 2%
Eldoquin Forte 4%
Nadinola 2%
Eldopaque Forte
4%
Esoterica 2%
Solaquin Forte
4%Solaq
uin Forte 4%
Porcelan
a 2%Nudit 2
%Melanex 3
%T
ota
l P
en
etr
ati
on
(µ
g)
Formulation Mean ± SE
Hydroquinone Products
(HPLC)
Hydroquinone Absorption
0 10 20 30 40
0
2
4
6
8
10
12
14
Flu
x (
g/cm
2 /hr)
Hours
Melanex (3% HQ)
Eldoquin Forte (4% HQ)
Hydroquinone Absorption
EF 10 min Mx 10 min EF 4 hr Mx 4 hr0
5
10
15
20
25
30
35
40
45
Hydroquinone Blister Data Summary
5 subjects
Dosed before BlisteringDosed after Blistering
31.56±11.18
4.43±2.27
5.55±5.05
0.52±0.36Conce
ntr
atio
n (
µg/m
L)
Drug/Dosing
Mean ± se
RETINOIDS
Veh SC Epi Dermis
IVRT
IVPT
Lehman PA, Franz TJ: Assessing the bioequivalence of topical retinoid products
by pharmacodynamics assay. Skin Pharmacol and Physiol 25:269-280, 2012.
TEWL
Skin Irritation
0 5 10 15 20
5
10
15
20
TEWL
TE
WL
Study Day
0
2
4
6
8
10
0.1% Retin-A Cream
Chro
mam
ete
r
Erythema
0
1
2
3
Peeling
Peelin
g S
core
Validation: TEWL Test
Tretinoin Gels
Two Primary Endpoints: (1) maximum transepidermal water loss achieved
(2) days to full peel (DTFP)
Tretinoin Gel: TEWL/Exfoliation
0 5 10 15 20 25
0
2
4
6
8
10
0.025% gel
0.010% gel
Placebo gel
Rela
tive T
EW
L (
g/m
2/h
r)
Study Day
Validation: TEWL Test
Tretinoin Gels Maximum TEWL
8
10
12
14
16
18
20
Placebo 0.01 0.025
Generic
Innovator
Product Labeled Potency (% Tretinoin)
TE
WL
max (g
/m
2/h
r)
Validation: TEWL Test
Tretinoin Gels Statistical Analysis
Dose = 0.01%
Classical CI on ratio (test/ref)
¤TEWL: (93.9%, 114.7%)
¤DTFP: (95.8%, 103.5%)
Dose = 0.025%
Classical CI on ratio (test/ref)
¤TEWL: (97.8%, 121.03%)
¤DTFP: (96.3%, 105.2%)
Summary
Assessment of the BE of topical drug products can be
accomplished through the use of appropriately selected in
vitro and in vivo surrogate tests.
All surrogate tests have limitations but they all don’t have the
same limitation. The results from one test complement the
results of other tests.
Selection of tests would depend upon the complexity of the
formulation and whether the test product is Q1/Q2 equivalent.
For most products IVRT, IVPT, and irritation testing would be
essential.
Recommended