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 in“Drug 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. … [O]ther 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. 42:338-44, 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. 30:1188-94, 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 < 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 25:1663-7695, 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. 93:2064-2075.

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