Bioequivalence Testing for Locally Acting Gastrointestinal Drugs: Scientific Principles

1. 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

2. 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;…

3. BE: The Crucial Market Place Pharmaceutical Standard

4. 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.

5. 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

6. PK Sample Plasma concentration • Efficacy at the site of action • Safety Pharmacokinetic BE Formulation Performance Dissolution Absorption Dose Systematically acting drugs

7. Classical BE

8. BE Paradigm

9. 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.

10. BCS Essential Idea

11. Maximum Absorption Rate

12. Drug Absorption: Fick’s 1st Law Applied to a Membrane

13. Diffusion vs.Pharmacokinetic Views Pharmacokinetic Diffusion Software e.g GastroPlus®

14. Drug Absorption at any Site • dM/dt(1/A) = Peff*C • 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

15. BE Paradigm Shift

16. PK Sample Plasma concentration Safety GI Drugs Formulation Performance Dissolution Absorption Dose Efficacy at the site of action Locally acting GI drugs: disconnection between the PK sample and the effectiveness

17. 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

18. Role of In VitroStudy 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).

19. In Vitro BE Dissolution • pH dissolution profile: • Suitable for pH dependant dissolution through a pH dependant coating • Surfactant changes: • Suitable for poorly soluble compounds

20. Dissolution pH Testing • Gastric pH and time • Small Intestinal pH range • Similar (f2) profiles

21. 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.

22. Example of Mesalamine – biopharmaceutical properties Three major factors to consider for developing an in-vitro BE test: 1. Solubility: - 1.996 mg/mL at 20°C - 3.216 mg/mL at 30°C - 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

23. PBS pH 6.8 SGF PBS pH 7.2 PBS pH 7.8 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.

24. 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.

25. 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?

26. BE Paradigm Shift

27. End