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.