Preventing Alcohol Induced Dose Dumping is a Desired Product Design Feature

1. ACPS Meeting October 26 2005 Preventing Alcohol Induced Dose Dumping is a Desired Product Design Feature Ajaz S. Hussain, Ph.D. Deputy Director, OPS/CDER/FDA

2. Points to Consider and Questions • Developing a regulatory decisional framework to minimize the risk of alcohol-induced dose dumping; • Should this be similar to current regulatory decision criteria for food-drug or drug-drug interactions? Or, • Should this leverage the “quality by design” approach to assess dose dumping potential (“rugged” vs “vulnerable”)? • What should be the criteria for • Distinguishing between “rugged” and “vulnerable” • regulatory consequence of developing a “vulnerable” product.

3. Preferred Approach? • An in vivo pharmacokinetic study examining whether there is an alcohol-formulation interaction is not the preferred approach • Pharmacokinetic studies in healthy subjects that involve co-administration of high alcohol loads (to emulate a “worst case” scenario) and a modified-release product may pose a risk, either due to the alcohol load itself and because of the potential for dose dumping in cases where the high exposure itself may be dangerous. • Although, for some drugs a pharmacologic antagonist can be used to reduce risks posed by dose dumping (e.g., for opiates, a naltrexone or nalaxone block), this approach may not be feasible or provide an adequate protection for most drugs.

4. Preferred Approach? • In case of food-induced dose dumping, the FDA guidance clearly recognizes that (unless the product is well designed) food effect studies can pose a risk to study subjects - “co-administration with food can result in dose dumping, in which the complete dose may be more rapidly released from the dosage form than intended, creating a potential safety risk for the study subjects” (2). • To be consistent with these FDA principles - intended to minimize risk to subjects – reliable alternate approaches to an in vivo evaluation are preferred

5. Preferred Approach • Clinical risk evaluation • Evaluation of product and manufacturing process design (Rugged, Vulnerable, Uncertain) • Prioritization of currently marketed products for testing • “Worst case” dissolution test • 40% V/V EtOH • Why should this be considered “worst” case? • Need for a more sophisticated system? • Leverage available In Vivo data

6. The Triggering Case: Drug Release Profile as a Function of Ethanol Concentration % Drug Released Vulnerable Time in Hours DPA/FDA Data

7. Example of “Rugged” Product Design % Drug Released Time in Hours DPA/FDA Data

8. Example #2: Vulnerable Product Design % Drug Released Time in Hours DPA/FDA Data

9. Assessment of “ruggedness’ • A formulation scientist (Dr. Mansoor Khan) was asked to analyze products systematically with respect to their composition, design, release mechanisms, analysis of anticipated weakest link, and categorized into “rugged”, “vulnerable” and “uncertain” categories • Laboratory testing by DPA to verify the classification

10. Predicted Vs. Experimental • Controlled release matrix tablets, release mechanism diffusion (Higuchi’s square root of time kinetics). • Vulnerability will depend upon the compression employed. • Anticipated performance: Rugged (if the tablets are hard)

11. Predicted Vs. Experimental • Multiparticulate beads in XXX technology. • The dissolution modeling indicated a good correlation with Two-Third model that implies a changing surface area of beads during dissolution. • Anticipated performance: Vulnerable

12. Predicted Vs. Experimental • Very specialized formulation with a matrix based design for waxy granules and a XXX coating. • While the ingredients are soluble in alcohol, the product design renders the “matrix” insoluble because of the compression and a gel like coating with XXX. • Anticipated performance: Rugged

13. Summary & Next Steps • Developing a regulatory decisional framework to minimize the risk of alcohol-induced dose dumping; • Leverage the “quality by design” approach to assess dose dumping potential (“rugged” vs “vulnerable”) • (+) “worst case” dissolution test (test of hypothesis) • The class boundary between “rugged” and “vulnerable”? • “f2 – profile comparison” or clinical/pharmaceutical risk assessment? • Regulatory consequence of developing a “vulnerable” product • non-approval, withdraw product from market, change AB rating, change labeling…? • Next steps • Existing products complete analysis • Expectations for new product