# Presentation: 422148

## Individual Bioequivalence:Background and Concepts

- Mei-Ling Chen, Ph.D.Associate Director
-  Office of Pharmaceutical Science

**Advisory Committee for Pharmaceutical Science**

- November 28-29, 2001
- Rockville, MD

##           Individual Bioequivalence                       Advantages

- Compares both population means and variances
- Considers subject-by-formulation interaction
- Establishes goalposts based on the reference variability for highly variable drug products
- Creates incentive for both innovators and generic sponsors to manufacture less variable products
- Encourages use of heterogeneous subjects that are more representative of the general population

##  Individual Bioequivalence Assessment		      Distance Concept

- Individual Difference Ratio (IDR)             Difference between T and R
- IDR = -------------------------------------             Difference between R and R’
- Both T and R are administered to the same individual
- Goal: IDR not substantially greater than 1

##             Individual Bioequivalence		

-            (**Average Difference)****2**** + Variance Terms**
**    ****------------------------------------------------------ **** BE Limit**                       **Reference Variance**** **
- T -  R)2 + D2 + (WT2 - WR2)
-    -------------------------------------------  I                     WR2
**    ****Variance Terms**** ****	**- Subject-by-formulation interaction ( D2 )	- Within-subject variances (WT2, WR2)** **

##               Subject-by-Formulation Interaction

- The S x F interaction is a measure of the extent to which the individual mean differences, Tj - Rj, between the T and R products are likely to differ.
- D2 = variance of (μTj -  μRj)
-           = (BT - BR)2 + 2 (1- ) BT BR
- μTj, μRj         	: individual-specific means
- BT, BR	: between-subject standard deviations
-   	         	: correlation coefficient between μTj & μRj
- D2	       	: S x F interaction variance component

##       Sources of S x F Interaction

-     D2 = var (μTj -  μRj)
-           = (BT - BR)2 + 2 (1- ) BT BR
- Changes in between-subject variability for T and R formulation
- Lack of congruence in individual means between T and R  formulation

##          Verapamil Immediate Release               Age-based SxF Interaction

**         ****Verapamil Immediate Release****               *****Age-based SxF Interaction***

**  *****SxF interaction occurred to Generic 1, but not Generic 2.**
**           ****Reference: Carter BL et al., Pharmacotherapy, 13, 1993**

##             Calcium Channel Blocker        Gender-based S x F Interaction

-             **Calcium Channel Blocker****  *****      Gender-based S x F Interaction***

##                 Interpretation of S x F Interaction

**Approach 1**Percentage of individuals whose average T/R ratios lie outside the range of 80-125%
**Approach 2**Presence of a subgroup(s) with a different average T/R ratio(s) from the remaining subjects of the population
*    *

##                  Approach 1

-                  **Approach 1**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**% **

**0.1**

**0.15**

**0.2**

**0.25**

**0.3**

**0.35**

**0.4**

**Sigma D Value**

* *

-                           ** ****Approach 2****           S x F Interaction Due to Subgroups**

##     Individual Bioequivalence Criterion

**  ****    **
**      **(T -  R)2 + D2 + (WT2 - WR2)
-     -------------------------------------------  I                     WR2
- Reference Scaling
- Away from the “one-size-fits-all” approach
- Goalposts adjusted for highly variable drug products** **

##          Mixed-Scaling Approach

-          **Mixed-Scaling Approach**

**Reference-Scaled (if ********WR**** > ********W0**** )****   **(T -  R)2 + D2 + (WT2 - WR2)
-     -------------------------------------------  I                     WR2
**Constant-Scaled (if ********WR**** ******** ********W0**** )**** **
**     **** **(T -  R)2 + D2 + (WT2 - WR2)
-     -------------------------------------------  I                     W02

##      Constraint on Mean Difference

-      **Constraint on Mean Difference**

-       (T -  R)2 + D2 + (WT2 - WR2)
-     -------------------------------------------  I                     WR2
- Incentives for manufacturing less variable formulations
- Mean-variance tradeoff
- Possibility of a large mean difference
- Guidance recommendation - Further constraint on the point estimate of geometric T/R mean ratio to be within 80-125%

## Replicate Design Studies:NDA’s and FDA Database

- Mei-Ling Chen, Ph.D.Associate Director
-  Office of Pharmaceutical Science

**Advisory Committee for Pharmaceutical Science**

- November 28-29, 2001
- Rockville, MD

##        Replicate Design Data           NDAs and ANDAs

**       ****Replicate Design Data****       *****    NDAs and ANDAs***

##               Old Database

**              ****Old Database**

**                   **

-   N= 17- 93

**New Data**

**       **

**Modified Release Products - NDAs**

## Immediate Release Products - NDAs

**Immediate Release Products - NDAs**

## IR - Data Set #2

**IR - Data Set #2**

**Subject  #9**

##          FDA Contract Studies

- Replicated-Crossover Design
- Conducted at the University of Tennessee
- Ranitidine
- Metoprolol
- Methylphenidate

## Interplay of Drugs and Excipients

- R

**Excipient 1****Sorbitol****Low permeability**
**  ********Osmotic pressure********GI transit time**

**Drugs**

**Ranitidine     **

**Metoprolol**

**(Low P)**

**(High P)**

**Excipient 2**
**Sucrose****High permeability**

**  ****Bioavailability?****  SxF Interaction?**

##               Excipient Effect                  Hypothesis

- The bioavailability of a low permeability drug (e.g., ranitidine) is more likely to be affected by an excipient such as sorbitol that reduces the gastrointestinal transit time.
- Subject-by-formulation interactions may occur when two syrup formulations contain different sweetening agents, e.g., sorbitol versus sucrose.

##               Ranitidine Levels

- Failed ABE and IBE AUCinf, T/R = 0.56  Cmax, T/R = 0.49

- (reference)

**(test)**

- Hussain AS, et al., AAPS Annual Meeting, 2000.

##            Metoprolol Levels 

- (reference)

- AUCinf, T/R = 0.93  Cmax, T/R = 0.77
- AUCinf Passed ABE & IBE
- Cmax Failed Both

- (test)

- Hussain AS, et al., AAPS Annual Meeting, 2001.

## Ranitidine in Sucrose vs. Sorbitol Solution             Subject-by-Formulation Interaction

**Reduction of between-subject variability from sucrose****  to sorbitol resulted in an SxF interaction (********D ****= 0.15)**

******BR****= 0.24**

******BT****= 0.13**

- Hussain AS, AAPS Annual Meeting, 2000.

##             Methylphenidate

-             **Methylphenidate**