# Presentation: 832826

## Bioequivalence of Locally Acting GI Drugs

- Robert Lionberger
- Office of Generic Drugs

## Dissolution

- Dissolution controls delivery to the site of action

## Pharmacokinetics

- Pharmacokinetic (PK) studies of locally acting drugs are related to safety
- A common claim: PK of locally acting drugs is not correlated with therapeutic effect.
- While this statement is often true, we need to carefully consider its implications for bioequivalence testing.
- PK of GI acting drugs is related to formulation performance

## Mesalamine

- Introduction
- Anti-inflammatory targeting colon
- Rapidly absorbed from intestine
- Can be measured in plasma
- Extensively metabolized in gut wall

## Formulation Approaches

- Pro-drug
- sulfasalazine (Azulfidine)
- balsalazide (Colazal)
- olsalazine (Dipentum)
- Delayed Release
- Asacol
- Pentasa

## Sulfasalazine

- Sulfasalazine (SS) Cleaved in the colon to form
- sulfapyridine (SP)
- mesalamine (5-ASA)
- 81% of SS and SP is recovered in urine
- SP is quickly absorbed
- 5-ASA is further metabolized

## PK for Bioequivalence

- SP was used for BE study endpoint
- Not further metabolized
- Rapidly absorbed
- Lower variability

## Pentasa

- Slow release coated microgranule formulation
- Releases throughout the intestine (Duodenum, jejunum, ileum, and colon)
- 60% release in the intestine
- 23% absorbed

## Pentasa Bioequivalence

- PK study attempted for bioequivalence between pilot and production scale products
- Replicate design because of high variability
- IVIVC established to demonstrate future equivalence of formulations

## Asacol

- Delayed release coated formulation
- pH sensitive dissolution ( pH 7 or greater)
- Release in terminal ileum and colon

## Dissolution Studies of Mesalamine

- M. W. Rudolph, S. Klein, T. E. Beckert, H. Petereit, and J. B. Dressman. A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis. *Eur J Pharm Biopharm*, 51(3):183–190, May 2001.

## Comparative PK

|  | Cmax | AUC |
| --- | --- | --- |
| Pellet | 429 +/- 262 | 968 +/- 629 |
| Tablet | 1241 +/- 1305 | 2205 +/- 1767 |

## Clinical Comparisons

- Clinical studies have not demonstrated significant difference between existing formulations (Sandborn 2002)

| N | Balsalazide | Asacol |
| --- | --- | --- |
| 101 | 62% | 45% |
| 98 | 65% | 53% |
| 173 | 52% | 49% |

- W. J. Sandborn, Rational selection of oral 5-aminosalicylate formulations
- and prodrugs for the treatment of ulcerative colitis, Am J Gastroenterol
- 97(12), 2939 (Dec 2002),

|  | Placebo | Asacol 0.8 g/d | Asacol 1.6 g/d |
| --- | --- | --- | --- |
| N | 63 | 58 | 68 |
| Success | 39.7% | 58.8% | 65.5% |

**An Oral Preparation of Mesalamine as Long-Term Maintenance Therapy for Ulcerative Colitis **
**A Randomized, Placebo-Controlled Trial. **
- Hanauer, et al, Ann Int Med, (124) 204-211,1996

## Mesalamine Summary

- How to distinguish current products
- Dissolution (yes)
- PK (likely, but high variability)
- Clinical comparison (challenging)

## Acarbose 

- Intestinal enzyme inhibitor to reduce glucose absorption
- No measurable absorption
- Pharmacodynamic endpoint
- Changes in glucose and/or insulin

## Cholestyramine

- Lowers cholesterol by bile acid sequestering
- No detectable absorption
- 1993 Guidance
- In vitro binding assay to demonstrate bioequivalence
- Measured affinity and capacity

## BCS Classification

- Systemic Drugs
- High permeability and high solubility drugs in rapidly dissolving dosage forms are eligible for waivers of in vivo bioequivalence studies
- Extend to GI acting drugs?
- High solubility drugs in rapidly dissolving dosage forms are eligible for waivers of in vivo bioequivalence studies

## Role of PK: Systemic

## Role of PK: GI acting

## Potential Framework

- Dissolution testing
- Conditions chosen based on understanding of formulation
- Pharmacokinetics/Pharmacodynamics
- Confirm dissolution testing
- Systemic exposure
- In vitro assay for excipient interactions
- Most relevant when mechanism of action is binding or sequestration

## Discussion

- Need ACPS input on
- Role of pharmacokinetic studies
- Role of *in vitro* dissolution tests
- Role of clinical studies

## Discussion Questions

- For locally acting GI drugs is PK, if measurable, an in vivo test sensitive to formulation performance and useful as a part of a determination of bioequivalence?
- What drug specific information would aid FDA in interpreting the results of a PK study on a GI acting drug with respect to a conclusion about bioequivalence?
- When is it possible to use dissolution testing alone to demonstrate bioequivalence of GI acting drugs?
- When should comparative clinical trial studies be conducted to demonstrate bioequivalence?
- Should BCS based biowaivers be granted for GI acting drugs?