Bioequivalence of Locally Acting Gastrointestinal Acting Drugs: Scientific Considerations

1
Bioequivalence of Locally Acting Gastrointestinal
Acting Drugs Scientific Considerations

• James E. Polli
• University of Maryland
• July 23, 2008

2
Low Solubility Immediate Release Dosage Forms of
Locally-acting GI Drugs

• What role should biorelevant dissolution play in
  developing BE recommendations for low solubility
  locally acting drugs that treat GI conditions?
• What role should systemic pharmacokinetics play
  in developing BE recommendation for low
  solubility locally acting drugs that treat GI
  conditions?

3
In Vitro Studies in Assessing IR BE for
Systemically-acting Oral Products

• 1. Reduce costs
• Avoid in vivo studies where BE is self-evident,
  where biopharmaceutic data anticipates BE, and
  where in vivo BE study type II error is high
• 2. More directly assess product performance
• In vitro studies allow for focus on product
  performance, which is dissolution and absorption.
• Conventional BE testing suffers from
  complications (e.g. HVD) due to its indirect
  approach.
• 3. Offer benefits in terms of ethical
  considerations
• Better embraces No unnecessary human testing
  should be performed
• Can result in faster development

Polli, J.E. (2008) In Vitro Studies Are
Sometimes Better than Conventional Human
Pharmacokinetic In Vivo Studies in Assessing
Bioequivalence of Immediate-release Solid Oral
Dosage Forms. AAPS J.
4
Differing Goals

• Formulation performance evaluation
• Bioequivalence means the absence of a
  significant difference in the rate and extent to
  which the active ingredient or active moiety in
  pharmaceutical equivalents or pharmaceutical
  alternatives becomes available at the site of
  drug action when administered at the same molar
  dose under similar conditions in an appropriately
  designed study. CFR Title 21 Part 320
• Possible tests include pharmacokinetic studies,
  pharmacodynamic studies, clinical studies, and in
  vitro studies
• Clinical safety/efficacy evaluation

5
Differing Goals

• Formulation performance evaluation is at least as
  discriminating as clinical safety/efficacy
  evaluation
• BE assures clinical safety and efficacy
• BE test is at least as accurate and precise as
  comparative clinical studies

6
Bioequivalent versusSafe and Effective
Not safe and effective
BE
Safe and effective
7
Issues inDrug M Clinical Studies

• Efficacy and/or tolerability of test and placebo
  are sometimes close
• Rates of improvement and underlying variability
• Variables
• disease severity
• instrument to measure efficacy
• definition of the primary end point
• Despite numerous studies investigating the
  effect of drug M dose on clinical efficacy, it
  remains unclear whether a dose-response for drug
  M exists. Other larger studies have not
  consistently shown a dose response for drug M
  above doses of 1.5 g/d.
• Sandborn WJ. Oral drug M therapy in ulcerative
  colitis what are the implications of the new
  formulations?. Journal of Clinical
  Gastroenterology. 42338-44, 2008.

8
Locally-acting Drugs

• Do locally-acting drugs know they are not suppose
  to be systemically-acting ?

9
BE of Most Products(i.e. Systemic Exposure)

• Conventional human pharmacokinetic in vivo BE
  study
• For orally administered products, site of action
  in systemic tissue extends beyond plasma
• Extrapolation assumption
• Extrapolate forward from plasma data
• Same A, hence same ADME, and hence
  therapeutically equivalent

10
Extrapolation vs Interpolation
drug dissolution
drug dissolution
Question 1
drug in plasma
drug in tissue
drug in plasma
Question 2
drug in tissue
Assume drug dissolution required for drug action
11
BE of Locally-acting GI Products

• Conventional human pharmacokinetic in vivo BE
  study?
• For such orally administered products, site of
  action precedes plasma
• Interpolation assumption (or extrapolate back
  and/or extrapolate forward)?
• Interpolate between dissolution and plasma data
• Extrapolate forward from (in vitro) dissolution ?
• Extrapolate back from plasma data ?

12
Plasma Concentration and Formulation Performance

• Indicative of formulation performance?
• Do similar plasma profiles assure similar
  concentration at site of action?
• How do you know where drug is released?
• Total exposure, peak exposure, and early exposure
• To use plasma only, probably need a minimum level
  of systemic exposure
• Plasma alone would not differentiate between
• Product 1 performs (with no systemic exposure)
• Product 2 completely fails to release

13
Plasma Concentration and Formulation Performance

• Indicative of formulation performance?
• Local excipient effects not captured by plasma
  profiles?
• Metabolite issues

14
In Vitro Dissolution and Formulation Performance

• Indicative of formulation performance?
• In vivo dissolution is the primary factor in
  luminal tissue exposure
• In vitro dissolution testing must reflect
  relevant in vivo parameters
• Relevant parameters depend upon drug and
  formulation
• Low solubility drugs are more complex
• Do similar in vitro dissolution profiles assure
  similar concentration at site of action?

15
Clinical Studies andFormulation Performance

• Indicative of formulation performance?
• Comparative clinical studies can fail to be
  sensitive to formulation differences, including
  bioinequivalent situations

16
Establishment of Biomarkers for Local Delivery to
the GI Tract

• Potential biomarker
• In vitro dissolution
• Plasma concentration
• Target/evidence
• In vivo dissolution
• Local tissue level
• Plasma concentration
• Formulation design

17
Establishment of Biomarkers for Local Delivery to
the GI Tract

• To accept combined in vitro dissolution and
  plasma concentration as BE method for different
  formulations, requires interpolation assumption
• To accept plasma concentration as sole BE method
  for different formulations, requires
  extrapolate-back assumption
• To accept in vitro dissolution alone as BE
  method, compare in vitro dissolution to in vivo
  dissolution or local tissue level
• or to plasma concentration in an IVIVC-like
  approach using fast, medium and slow formulations
• IVIVCs for MR formulations are considered
  formulation specific
• What about IR products?

18
Intestinal Luminal Microdialysis

• In pigs, glycerol, lactate and glucose in the
  intestinal lumen and mucosa were measured by
  microdialysis
• Release of lactate into the intestinal lumen may
  be useful for monitoring intestinal ischemia.
• E. Solligard et al. Gut barrier dysfunction as
  detected by intestinal luminal microdialysis.
  Intensive Care Medicine. 301188-94, 2004.

19
Positron Emission Tomography (PET)

• Imaging of compounds labeled with 11C, 13N, 15O
  or 18F
• e.g. distribution of 18F-deoxyglucose to brain
• PET attributes
• Absolute quantification in vivo, even after
  microdose
• Resolutions of lt 5mm in tissues
• Scaling from preclinical to clinical
• Pharmacologically identical to non-radiolabeled
  drug
• Considered non-invasive
• Short half-lives of radionuclides
• 11C, 13N, 15O, and 18F, are 20min, 10min, 2min,
  and 1.8hr, respectively
• Major limitation to formulation studies

20
Roles of Dissolution Testing

• Formulation development tool
• May purposely provide a challenging media
  conditions
• Biomimetic test (use biorelevant dissolution
  media)
• Intends to mimic gastrointestinal luminal
  conditions (e.g. composition, physiochemical
  characteristics)
• e.g. FaSSIF-V2
• Quality control test
• e.g. RLD regulatory method
• Bioequivalence surrogate
• e.g. the BCS panel method justified via IVIVC
  analysis

21
Low Solubility Drugs

• More challenging
• Ionization effects
• Increased solubility in micellar solutions
• Solubility and dissolution in in vivo fluid
  generally much larger than aqueous solubility

22
Possible Biorelevant Dissolution Media

• Preprandial stomach
• SGF USP (pH 1.2) without enzyme
• SGF USP plus surfactant (e.g. 0.1 Triton X) plus
  perhaps pepsin
• Postprandial stomach
• Ensure Plus bovine milk 3.5 fat
• Preprandial jejunum
• FaSSIF
• Fasted State Simulated Intestinal Fluid
• Postprandial jejunum
• FeSSIF
• Fed State Simulated Intestinal Fluid

23
Updated Biorelevant Media

• Jantratid E, Janssen N, Reppas C, and Dressman
  JB. Dissolution Media Simulating Conditions in
  the Proximal Human Gastrointestinal Tract An
  Update. Pharm Res 251663-7695, 2008.
• The aim of this study was to update the
  compositions of biorelevant media to represent
  the composition and physical chemical
  characteristics of the gastrointestinal fluids as
  closely as possible while providing physical
  stability during dissolution runs and short-term
  storage.
• Fasted stomach (denoted FaSSGF from recent
  publication)
• Postprandial stomach (denoted FeSSGF new medium)
• Fasted upper small intestine (denoted FaSSIF-V2
  modified from FaSSIF)
• decreased lecithin, lower osmolality, and
  substitution of maleate for phosphate buffer,
  NaCl rather than KCl
• Fed upper small intestine (denoted FeSSIF-V2
  modified from FeSSIF)
• pH increased from 5.0 to 5.8, lower osmolality,
  decreased sodium taurocholate and lecithin, added
  glyceryl monooleate, maleate rather than
  phosphate buffer, NaCl rather than KCl

24
Drug X Dissolution Profiles in Various Media at
100 rpm
25
Synthetic Surfactants

• Validation of the correspondence of results in
  media containing synthetic surfactants with those
  containing bile components is necessary on a
  case-by-case basis.
• T Zoeller and S Klein. Simplified Biorelevant
  Media for Screening Dissolution Performance of
  Poorly Soluble Drugs. Dissolution Technologies
  Nov. 8-13, 2007.

26
Solubilization vs Diffusion

• To assess the contributions of surfactant-mediated
  solubility and micellar diffusivity on the
  ability of surfactant to enhance drug
  dissolution.

Balakrishnan, A., Rege, B.D., Amidon, G.L., and
Polli, J.E. (2004) Surfactant-mediated
dissolution contributions of solubility
enhancement and relatively low micelle
diffusivity. J. Pharm. Sci. 932064-2075.
27
Enhancement of griseofulvin solubility and
dissolution by SDS and CTAB
28
Data

• For low solubility drugs, regulatory requirement
  for dissolution in specific media?
• e.g. BCS media with SLS
• Dissolution Test Method Report
• Contains the justification for a particular
  dissolution test method to serve as the QC
  dissolution test

29
Summary for Low Solubility IR Locally-acting GI
Drugs

• In vitro studies have potential to sometimes
  better serve as BE tests than in vivo studies
• Low solubility drugs are more difficult
• No universal in vitro test
• Biorelevant dissolution media refers to designed
  media (with future promise)
• More research needed
• Data needed for a proposed (set of) media

30
Summary for Low Solubility IR Locally-acting GI
Drugs

• What role should biorelevant dissolution play in
  developing BE recommendations for low solubility
  locally acting drugs that treat GI conditions?
• In general, in vitro dissolution only cannot be
  suggested to serve as the BE test for low
  solubility drugs
• What role should systemic pharmacokinetics play
  in developing BE recommendation for low
  solubility locally acting drugs that treat GI
  conditions?
• Given current options beyond clinical study, an
  apparent necessity
• On a drug-by-drug basis, has potential to be as
  reliable as PK studies used for systemically
  acting drugs
• What role should combined dissolution and PK
  play?
• Potentially very strong case since data addresses
  formulation performance
• Requires interpolation assumption and
  justification for the proposed dissolution test
  across differing formulations