Bioequivalence Testing for Locally Acting Gastrointestinal Drugs: Scientific Principles

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Bioequivalence Testing for Locally Acting
Gastrointestinal Drugs Scientific Principles

• Gordon L. Amidon, Ph.D.
• Professor of Pharmaceutical Sciences
• College of Pharmacy
• The University of Michigan

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Bioequivalence (BE) Orange Book

• the rate and extent of absorption of the test
  drug do not show a significant difference from
  the rate and extent of absorption of the
  reference drug when administered at the same
  molar dose of the therapeutic ingredient under
  similar experimental conditions in either a
  single dose or multiple doses

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BE The Crucial Market Place Pharmaceutical
Standard
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Locally Acting Drugs Orange Book

• Where these above methods are not applicable
  (e.g., for drug products that are not intended to
  be absorbed into the bloodstream), other in vivo
  or in vitro test methods to demonstrate
  bioequivalence may be appropriate.

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BE Testing GI Drugs

• Plasma concentration may not reflect the
  therapeutic effect, while it may indicate safety.
• Concentration at the local GI tract site is not
  easily measured directly.

• Key Scientific Principles for the Following
  Issues
• Role of Pharmacokinetic (PK) Studies
• Role of In Vitro Studies
• Role of Clinical Studies

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Pharmacokinetic BE
Formulation Performance
Absorption
Dissolution
Dose
Systematically acting drugs
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Classical BE
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BE Paradigm
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BCS approach to BE

• If two drug products, containing the same drug,
  have the same concentration time profile at the
  intestinal membrane surface then they will have
  the same rate and extent of availability at the
  site of action.
• If two drug products have the same in vivo
  dissolution profile under all luminal conditions,
  they will have the same rate and extent of
  availability at the site of action.

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BCS Essential Idea
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Maximum Absorption Rate
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Drug Absorption Ficks 1st Law Applied to a
Membrane
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Diffusion vs.Pharmacokinetic Views
Pharmacokinetic
Diffusion
Software e.g GastroPlus
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Drug Absorption at any Site

• dM/dt(1/A) PeffC
• dM/dt (1/A)at that point
• Peff(x,y,z,t, excipients) at that point
• May be affected by drug and excipients if in
  direct contact
• C(x,y,z,t)at that point

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BE Paradigm Shift
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GI Drugs
Formulation Performance
Absorption
Dissolution
Dose
Efficacy at the site of action
Locally acting GI drugs disconnection between
the PK sample and the effectiveness
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BE of GI Local Drugs

• Plasma concentration is down stream from site of
  clinical effect.
• Local site of action in GI Tract.
• Dissolution and transit in vivo controls
  presentation of drug to site of action
• Low Permeability Drugs
• Low Systemic Availability

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Role of In Vitro Study

• For locally GI acting drugs,
• In vivo dissolution is the key determinant of
  presentation of drug to site of action.
• In vitro dissolution testing must cover the range
  of the in vivo variables.
• Biowaiver for BCS I drugs is applicable to GI
  locally acting drugs (GE Limited).

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In Vitro BE Dissolution

• pH dissolution profile
• Suitable for pH dependant dissolution through a
  pH dependant coating
• Surfactant changes
• Suitable for poorly soluble compounds

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Dissolution pH Testing

• Gastric pH and time
• Small Intestinal pH range
• Similar (f2) profiles

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Role of in vitro Studies Is Biowaiver
applicable?

• Biowaivers for BCS class I drugs in immediate
  release solid oral dosage forms are well
  established.
• If two drug products, containing the same drug,
  have the same concentration time profile at the
  intestinal membrane surface then they will have
  the same rate and extent of availability at the
  site of action.
• If two drug products have the same in vivo
  dissolution profile under all luminal conditions,
  they will have the same rate and extent of
  availability at the site of action.

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Example of Mesalamine biopharmaceutical
properties

• Three major factors to consider for developing an
  in-vitro BE test
• 1. Solubility
• - 1.996 mg/mL at 20C
• - 3.216 mg/mL at 30C
• - High solubility based on 250 mL volume and 500
  mg dose
• 2. Permeability May be less important as
  mesalamine is acting locally in GI tract.
• 3. Dissolution Reflect in-vivo dissolution to
  ensure BE.

Molecular structure of Mesalamine
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Examples of Mesalamine Formulations
Dissolution of mesalamine formulations in SGF and
phosphate buffers pH 6.8, 7.2 and 7.8 M.W.
Rudolph, S. Kevin, T. E. Beckert, H. Petereit and
J. B. Dressman, Eur. J. Pharm. Biopharm. 51 (3)
189-190, 2001.
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Role of Clinical Studies

• Conventional comparative clinical studies
• are used when PK/PD approaches are infeasible.
• are expensive and insensitive to formulation
  difference.
• Innovative clinical studies
• measure the concentration along the GI mucosal
  lining.
• are sensitive to formulation changes and
  reflective of
• in-vivo dissolution.
• are still expensive.

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Topic 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?
• Are there any drug specific issues that 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 BE of GI acting drug
  products?
• When should comparative clinical studies be
  conducted to demonstrate BE?
• When the food-effect studies be considered?

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BE Locally Acting GI Drug Proposal

• In Vitro Dissolution Test
• In Vivo point estimate within 90-110 of reverence.

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BE Paradigm Shift
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End