1. Bioequivalence of Locally Acting GI Drugs
Robert Lionberger
Office of Generic Drugs

2. Dissolution Dissolution controls delivery to the site of action
Jejenum pH
Ileum pH
Stomach pH

3. 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

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

5. Formulation Approaches
Pro-drug
sulfasalazine (Azulfidine)
balsalazide (Colazal)
olsalazine (Dipentum)
Delayed Release
Asacol
Pentasa

6. 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

7. PK for Bioequivalence SP was used for BE study endpoint
Not further metabolized
Rapidly absorbed
Lower variability

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

9. 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

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

11. 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.

12. Comparative PK Cmax AUC Pellet 429 +/- 262 968 +/- 629 Tablet
1241 +/- 1305
2205 +/- 1767

13. 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%
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) ,1996
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),

14. Mesalamine Summary How to distinguish current products
Dissolution (yes)
PK (likely, but high variability)
Clinical comparison (challenging)

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

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

17. BCS Classification Systemic Drugs Extend to GI acting 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

18. Role of PK: Systemic

19. Role of PK: GI acting

20. 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

21. Discussion Need ACPS input on Role of pharmacokinetic studies
Role of in vitro dissolution tests
Role of clinical studies

22. 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?