Bioequivalence of Locally Acting GI Drugs

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Bioequivalence of Locally Acting GI Drugs

• Robert Lionberger
• Office of Generic Drugs

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Dissolution

• Dissolution controls delivery to the site of
  action

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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

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Mesalamine

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

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Formulation Approaches

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

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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

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PK for Bioequivalence

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

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Pentasa

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

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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

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Asacol

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

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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)183190, May 2001.
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Comparative PK
Cmax AUC
Pellet 429 /- 262 968 /- 629
Tablet 1241 /- 1305 2205 /- 1767
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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) 204-211,1996
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),
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Mesalamine Summary

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

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Acarbose

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

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Cholestyramine

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

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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

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Role of PK Systemic
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Role of PK GI acting
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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

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Discussion

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

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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?