# Presentation: 255778

## 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**

## Common GoalBest Therapeutic Products

***Innovator***
***Industry***

***Generic***
***Industry***

***Physicians***

***Consumer***

***FDA***

***Scientists***

***Health Care***
*** ******Insurance***

***CROs***

## Hypothesis

**The dermatopharmacokinetic (DPK) method **
**will assess the BIOEQUIVALENCE of **
**three 0.025% tretinoin gel products **
**similar to the **
**Clinical Efficacy/Safety Trial method**

## Bioequivalence

**How much **_**different**_** ****can two topical products be and still be **_**bioequivalent**_**?**

## BioequivalenceQ1 Q2 similar

- 	**Q1****	****	****	****	****	****Q2**
_**Qualitatively similar**__**	**__**	**__**Quantitatively similar**_**same ****	****	****	****	****	****same **
**Vehicle components****	****	****[Vehicle components]**

## Bioavailability Q1 Q2 different

- 	**Q1****	****	****	****	****	****Q2**
_**Qualitatively different**__**	**__**	**__**Quantitatively different**_**different ****	****	****	****	****different [active]**
**Vehicle components****	****	****different [Vehicle components]**

## 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)
 |

## Bioequivalence AssessmentClinical Efficacy/Safety Acne Trial

| Clinical 
Parameter | Ortho vs. Spear
Q1 Q2 similar | Ortho vs. Bertek
Q1 Q2 different |
| --- | --- | --- |
| Efficacy | BE | Not BE
Ortho > Bertek |
| Safety | BE | Not BE
Bertek 2X > Ortho |

## Topical Drug Delivery

## Adhesive disc

## SC Drug DispositionInfluence Of Weight Removed On Drug Concentration Gradient

## Bioanalytical Assay Validation

**	****	****	****	**_**Tretinoin**__**	**__**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****	**
**-70****o****C storage****	****4 week****	****	****4 week**
**Benchtop****	****2 hrs****	****	****2 hrs**
**Post-extraction**
**Autosampler****	****112 hrs****	****	****112 hrs**
**Freeze thaw ****	****1 cycle****	****	****1 cycle**

## Product Dosing: 0.025% Tretinoin Gel

***250 mcL syringe***

## DPK Experimental Design

*   **UPTAKE**	**ELIMINATION*

## Product Application Randomizationtretinoin gel, 0.025%

## 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 |

## Surface Area Considerations Treated Skin Site vs. Adhesive Disc 

## DPK Bioequivalencetretinoin gel, 0.025%

## DPK BioequivalenceTretinoin

## D_x0008_PK Bioequivalencetretinoin gel, 0.025%

## DPK BioequivalenceIsotretinoin

## D_x0008_PK Bioequivalencetretinoin gel, 0.025%

## DPK BioequivalenceTotal Retinoids

## 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 |

## DPK Method for Bioequivalence Assessment

**Objective**
**Sensitive**
**Discriminating **
**Precise**
**Accurate**
**Relevant**
**Scientifically**
**Clinically**
**Comparable PK method used for oral solid dosage products**

## CONCLUSIONSDPK 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**