112901 LKPershing

Bioequivalence Assessment of three 0.025% tretinoin gel products:

Dermatopharmacokinetic vs. Clinical Trial Methods

Lynn K. Pershing, Ph.D.

Department of Dermatology

University of Utah

Salt Lake City, UT 84132

112901 LKPershing

Common GoalBest Therapeutic Products

InnovatorIndustry

GenericIndustry

Physicians

Consumer

FDA

Scientists

Health Care Insurance CROs

112901 LKPershing

Hypothesis

The dermatopharmacokinetic (DPK) method

will assess the BIOEQUIVALENCE of

three 0.025% tretinoin gel products

similar to the

Clinical Efficacy/Safety Trial method

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BioequivalenceHow much different

can two topical products be and still be bioequivalent?

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BioequivalenceQ1 Q2 similar

Q1 Q2Qualitatively similar Quantitatively similarsame same Vehicle components [Vehicle components]

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Bioavailability Q1 Q2 different

Q1 Q2Qualitatively different Quantitatively differentdifferent different [active]Vehicle components different [Vehicle components]

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Tretinoin gel, 0.025%A

Ortho

Reference

B

Bertek

Test 1

C

Spears

Test 2

Butylated hydroxy toluene

Butylated hydroxy toluene

Butylated hydroxy toluene

Hydroxypropyl cellulose

Hydroxypropyl

cellulose

Hydroxypropyl cellulose

Alcohol 90% (w/w) Polyolprepolymer-2

Ethanol 83% (w/w)

Denatured with

tert-butyl alcohol and

brucine sulfate

Alcohol 90% (w/w)

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Bioequivalence AssessmentClinical Efficacy/Safety Acne Trial

Clinical Parameter

Ortho vs. SpearQ1 Q2 similar

Ortho vs. BertekQ1 Q2 different

Efficacy BE Not BEOrtho > Bertek

Safety BE Not BEBertek 2X > Ortho

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Topical Drug Delivery

DRUGSC EPI DERMIS SQ FAT

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Adhesive disc

#1-10 #11-200

100

200

300

400

500

600mean ± SDn = 48 skin sites

Skin Stripping Numberm

cg

str

atu

m c

orn

eu

m

D-squame™adhesive disc

1.3 cm diameter2.2 cm diameter

1 panel:10 discs/skin site

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SC Drug DispositionInfluence Of Weight Removed On

Drug Concentration Gradient

1-10 11-201

10

100

1000

% dose applied

% dose applied/mg SC

mg SC harvested

Total Retinoidsmean n = 3 subjects, 6 sites/subject

Skin Stripping Compartment

% d

ose

ap

plie

d

mg

str

atu

m c

orn

eum

har

vest

ed

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Bioanalytical Assay ValidationTretinoin Isotretinoin

• Recovery >89.7% >87.0%• Interferences None None• Linear regression 0.9963 0.9961• Accuracy >87% >85%• Precision < 8% <11%• Assay parameters

– Calibration stds 4-100 ng/mL 4-100 ng/mL– LOQ 4 ng/mL 4 ng/mL

• Stability– Pre-extraction

• -70oC storage 4 week 4 week• Benchtop 2 hrs 2 hrs

– Post-extraction• Autosampler 112 hrs 112 hrs• Freeze thaw 1 cycle 1 cycle

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Product Dosing: 0.025% Tretinoin Gel

A B C0

1

2

3

4

5mean ± SD weight of a 5 mcL dose

mg

250 mcL syringe

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DPK Experimental Design

60 minutes prior 7 minutes prior to drug application to drug applicationWash forearms Tapestripwith gentle the designatedliquid soap untreated control

skin sites 1.50Demarcate 1.00 (-3 hr)skin sites 0.50 (-6 hr)on forearms with (-9 hr)prepared template 0.25

(-12 hr)

0h

*

730 0755 0830 845 900 1000 1030 1330 1630 1930 2230drug applied to all skin sites

Key

* Application time 0 hr (0830 on day 1)

Drug Removal time 0.25, 0.50, 1.00 and 1.50 hours post drug application

Tapestrippping collection times 1hr prior to drug application 0.25, 0.5, 1, 1.5, 4.5, 7.5, 10.5 and 13.5 hr after drug application

UPTAKE ELIMINATION

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Product Application Randomizationtretinoin gel, 0.025%

A

BC

12

3 3

21

RIGHT LEFTWRIST WRIST

3

3

3

3

3

3

2

2

22

2

211

1

1

1

1

IV

III

II

I

VIII

VII

VI

V

3 cm 3 cm

hr

hr

hr

hr

3 cm

ANTECUBITALFOSSA

ANTECUBITALFOSSA

untreatedcontrol site

3 cm

UNT

UNT

UNT

3 cm

A

BC

A

BC

A

BC

A

BC

A

BC

A

BC

A

BC

Uptake Elimination

hr

hr

hr

hr

1.5

0.25

0.50

1.0

-6

-3

-9

-12

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BE Study Demographics

Subject # Gender Age (yrs)

Mean (SD)

Ethnicity Hand

Preference

29

20

Female

Male

31.2 (10.7)

29.5 (8.3)

25 C, 3 A, 1 H

16 C, 3 A, 1 H

29 R, 0 L

16 R, 4 L

49 TOTAL 30.7 (9.4) 41 C, 6 A, 2 H 45 R, 4 L

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Surface Area Considerations

Treated Skin Site vs. Adhesive Disc

Skin site

Adhesive disc

SC harvesting

1.2 cm 1.13 sq cm

1.3 cm 1.3 sq cm

1.3 cm 1.3 sq cm

mcg drug / 1.3 sq cm surface area

Diameter Surface area

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DPK Bioequivalencetretinoin gel, 0.025%

16128400

10

20

30

40

50

60

70

80

90

100

OrthoBertekSpears

Tretinoinmean, n = 49

Hours after product application

ng

/ s

q c

m

residual productremoval

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DPK BioequivalenceTretinoin

Parameter Bertek

Test

Ortho

Reference

Bioequivalence

90% CI

Bioinequivalence

95% CI

Cmax 68.394 105.335 67.6% – 83.9% 66.2% – 85.7%

AUC0-t 190.145 377.253 49.0% – 58.6% 48.1% - 59.6%

Spear

Test

Ortho

Reference

Bioequivalence

90% CI

Bioinequivalence

95% CI

Cmax 110.955 105.335 94.0% - 116.7% 92.1% - 119.2%

AUC0-t 391.654 377.253 97.0% - 115.9% 95.3%- 118.0%

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DPK Bioequivalencetretinoin gel, 0.025%

16128400

10

20

30

40

50

60

70

80

90

100

OrthoBertekSpears

Isotretinoinmean , n = 49

Hours after product application

ng

/ s

q c

m

residualproductremoval

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DPK BioequivalenceIsotretinoin

Parameter Bertek

Test

Ortho

Reference

Bioequivalence

90% CI

Bioinequivalence

95% CI

Cmax 38.020 51.647 67.6% – 83.9% 66.2% – 85.7%

AUC0-t 149.210 282.096 49.0% – 58.6% 48.1% - 59.6%

Spear

Test

Ortho

Reference

Bioequivalence

90% CI

Bioinequivalence

95% CI

Cmax 53.453 51.647 94.0% - 116.7% 92.1% - 119.2%

AUC0-t 294.124 282.096 97.0% - 115.9% 95.3%- 118.0%

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DPK Bioequivalencetretinoin gel, 0.025%

16128400

20

40

60

80

100

120

140

OrthoBertekSpears

Total Retinoidsmean, n = 49

Hours after product application

ng

/ s

q c

m

residualproductremoval

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DPK BioequivalenceTotal Retinoids

Parameter BertekTest

OrthoReference

Bioequivalence90% CI

Bioinequivalence95% CI

Cmax 106.117 155.414 61.3% – 77.8% 59.8% – 79.7%

AUC0-t 356.766 684.528 48.4% – 56.5% 47.6% - 57.4%

SpearTest

OrthoReference

Bioequivalence90% CI

Bioinequivalence95% CI

Cmax 165.450 155.414 94.6% - 120.2% 92.4% - 123.0%

AUC0-t 715.099 684.528 97.1% - 113.5% 95.6%- 115.2%

112901 LKPershing

Bioequivalence Assessment of Three 0.025% tretinoin gel products

Method

Ortho vs. Spears

Q1 Q2 similar

Ortho vs. Bertek

Q1 Q2 different

DPK BE Not BE

Ortho 2x > Bertek

Clinical Efficacy BE Not BE

Ortho > Bertek

Clinical Safety BE Not BE

Bertek 2x > Ortho

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DPK Method for Bioequivalence Assessment

• Objective• Sensitive• Discriminating • Precise• Accurate• Relevant

– Scientifically– Clinically

• Comparable PK method used for oral solid dosage products

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CONCLUSIONSDPK Method for Bioequivalence Assessment

0.025% tretinoin gel

• DPK results predict Clinical Efficacy Results• DPK provides mechanistic basis for Safety Results• DPK is sensitive, reproducible and valid method for

BE assessment