Bioequivalence of Poorly Soluble Locally Acting GI Drugs

1. Bioequivalence of Poorly Soluble Locally Acting GI Drugs Robert Lionberger Office of Generic Drugs ACPS-CP Meeting July 23, 2008

2. Stomach pH 1.4-2.1 Jejenum pH 4.4-6.6 Ileum pH 6.5-7.4 Why Does Solubility Matter? • In vivo dissolution controls delivery to the site of action • For high solubility drugs, equivalent in vitro dissolution in buffer (pH 1.2, 4.5, 6.8) ensures in equivalent vivo dissolution and supports biowaivers

3. Example Drug X; Highly soluble, IR tablet The test and reference list drug products have the same formulations, qualitatively and quantitatively

4. What is Low Solubility? • When the highest strength does not dissolve in 250 ml of aqueous media at any pH between 1 and 7.5 • Very conservative • Categories of low solubility drugs • Weak acid (only low solubility at low pH) • Weak base (only low solubility at high pH) • Reasonable solubility in vivo fluids • Truly poor solubility • Solubility limited absorption • Reduction in fraction absorbed with dose • Novel formulation technologies may be used

5. Pharmacokinetics/Absorption • GI acting drugs may or may not have significant absorption • Many can be detected systemically • Pharmacokinetic (PK) studies may be requested for safety • Rate of absorption is related to local GI concentration • in vivo formulation performance • Location of drug after release from IR dosage form is governed by GI transit S. Willmann, W. Schmitt, J. Keldenich, and J. B. Dressman Pharm Res, 20, 1766, 2003

6. Drug Release from Product Plasma Concentration Site of Action Effect Drug Release from Product Site of Action Effect Plasma Concentration BE for Locally Acting Drugs • Systemic action: drug in plasma -> BE • Local action: drug in plasma ->“side effect”

7. Introduction to Examples • For high solubility drugs, in vitro dissolution in buffer (pH 1.2, 4.5, 6.8) ensures in vivo dissolution and supports biowaivers • Low solubility drugs are more challenging • Ionization effects • Increased solubility in micellar solutions • Solubility and dissolution in in vivo fluid generally much larger than aqueous solubility • Does the in vitro test predict in vivo performance for low solubility drugs?

8. Example One • Drugs P (prodrug) and A (active) • A has site of action in colon • A is rapidly absorbed from intestine • Can be measured in plasma • Extensively metabolized in gut wall • Delivered to colon as a prodrug (P) • P is cleaved in the colon to form A • 12-35% of A is absorbed • <5% of P is absorbed

9. Solubility Prodrug Solubility Active Drug Solubility

10. Prodrug Dissolution

11. Potential Bioequivalence Methods • OGD Working Group considered • Dissolution • PK study (as a surrogate for local delivery) • Clinical end-point studies • Actions • Laboratory studies of dissolution • Simulations of GI transit, drug release, absorption, PK • Individual review and discussion of each product • BE recommendation • Dissolution of prodrug; fed and fasting PK of prodrug and active

12. BE Recommendations P released from formulation Dissolution measured A absorption fromcolon (site of action) PK of A measured Some P absorbed PK of P measured In colon, bacteria convert P to A Remaining P transits small intestine

13. P and A (Simulation) Simulations illustrate GI concentration/plasma concentration correlations for IR products Active Prodrug

14. Reflection • Is there a dissolution test that would eliminate the need for multiple PK studies? • For this product, dissolution was questioned because it lacked sequential exposure to low pH • Combination of dissolution and PK addressed this concern

15. Sequential Exposure Dissolution at pH 4.5 30 min at pH 1.2 Dissolution at pH 4.5

16. Example Two • Drug B • Solubility (pKa of 5.81) • < 0.1 mg/mL in 0.1 N HCl • 33-100 mg/mL in 0.1 N NaOH • ~33% of dose is absorbed • Absorbed drug may not reach local site of action • AUC increases supra-linearly with dose • Tablet and suspension formulations marketed and compared in clinical, PK and dissolution studies

17. Product Comparison

18. Dissolution Tablet Dissolution pH 7.5 6% of various surfactants Suspension Dissolution pH 7.5 6% of surfactant Regulatory methods (release tests) use non-physiological pH and surfactant concentrations

19. PK comparison (metabolite) PK profiles indicate drug is released from formulation and available for absorption in small intestine Suggests drug may be soluble in biorelevant media

20. Potential BE Approaches • Fed and fasted PK studies • Which dissolution media? • pH range and surfactant concentration range to provide most sensitive formulation comparison or • Biorelevant media

21. Reflection • What is the value of dissolution in 6% surfactant? • Role of inactive ingredients in suspension formulation • Detected in PK study • No significant clinical effect • Role of particle size • Detected in other PK studies

22. Current State to Next Step • For a particular product: in vitro dissolution + in vivo studies provided demonstration of BE (local delivery) for a low solubility drug • PK study: evidence of in vivo release • Next: How do we generalize this to other products? • High aqueous solubility in limited pH range • High solubility in biorelevant media • No high solubility in vivo

23. Next Step • High aqueous solubility in limited pH range • Recommend dissolution in aqueous buffers and PK or other study to confirm in vivo release • Contingent on site of action • Drug only soluble in biorelevant media • Recommend dissolution in biorelevant media and PK or other study to confirm in vivo release • Contingent on site of action • Drug not soluble in biorelevant media • Investigate mechanism for local availability

24. Desired State • Biorelevant dissolution to eliminate need for additional in vivo studies. • In vivo dissolution directly determines local GI concentration • Equivalent dissolution over the physiological range ensure BE over patient population. • Q1 and Q2 differences may lead to additional studies

25. How will we know when biorelevant dissolution is ready? • When biorelevant dissolution predicts in vivo dissolution (as assessed by drug absorption or imaging studies), then it is ready. • When biorelevant dissolution is used in QbD approaches to design the formulation of low solubility drugs, then it is ready.

26. Questions • 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?