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Clinical Relevance of Alcohol-induced Dose Dumping . Robert J. Meyer, MD Director, Office of Drug Evaluation II, OND/CDER. Clinical Relevance of Alcohol-induced Dose Dumping. Recent experience has shown that some modified-release formulations are defeated in vitro by alcohol

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clinical relevance of alcohol induced dose dumping

Clinical Relevance of Alcohol-induced Dose Dumping

Robert J. Meyer, MD

Director, Office of Drug Evaluation II, OND/CDER

clinical relevance of alcohol induced dose dumping2
Clinical Relevance of Alcohol-induced Dose Dumping
  • Recent experience has shown that some modified-release formulations are defeated in vitro by alcohol
  • In some cases, this can correlate with a clinically relevant effects documented in vivo
  • Talk will review some of this experience and some clinical thoughts on the importance of this issue
case background
Case Background
  • New, once-daily modified-release drug product of a reasonably narrow-therapeutic index drug with abuse liability
  • Tested prior to approval for abuse liability potential (ability to extract drug out of the formulation)
  • This testing showed that extended exposure to high concentrations of alcohol in vitro could extract the drug
  • However, dissolution testing done prior to approval used standard methods and did not explore alcohol effect
case presentation
Case Presentation
  • Post-approval, sponsor conducted a PK study to assess the interaction of various strengths of alcohol concomitantly administered
  • Alcohol tested was 8 oz (240 ml) of 40%, 20%, 5% and 0% (water)
  • These concentrations approximate the concentrations of whiskey, mixed drink and a European beer
case presentation5
Case Presentation

Results:

  • 40% alcohol with the drug led to a five-fold increase in Cmax
  • 20% led to a doubling of Cmax
  • 5% led to a small mean effect, but at least one subject doubled their Cmax
case presentation6
Case Presentation
  • Conclusion of FDA was that there was a significant alcohol – drug interaction
  • Demanded some risk minimization / action
    • More on this in subsequent slide
  • Regulatory learning that alcohol can undermine modified-release mechanisms
    • Implications for existing MR products
    • Implications for new MR products
clinical consideration of alcohol induced dose dumping
Clinical Consideration of Alcohol-Induced Dose Dumping

Existing Products:

  • Need to prioritize in vitro (+/- in vivo) testing
  • Based on:
    • Therapeutic index (consequences of high Cmax or low Cmin)
    • Population at risk
      • Extent of use, vulnerability of population
clinical consideration of alcohol induced dose dumping8
Clinical Consideration of Alcohol-Induced Dose Dumping
  • Existing products:
    • For products with clinical concern and positive in vitro test:
      • Labeling, along with
      • In vivo testing
      • If in vivo testing is concerning, further regulatory action will be needed
clinical consideration of alcohol induced dose dumping9
Clinical Consideration of Alcohol-Induced Dose Dumping
  • For products that are shown to be vulnerable and where implications are severe, what is the regulatory response?
    • Labeling (+/- MedGuide)
      • Limitations of effectiveness
    • More formal risk minimization plans
    • Withdrawal
clinical consideration of alcohol induced dose dumping10
Clinical Consideration of Alcohol-Induced Dose Dumping
  • Future MR products:
    • In vitro testing for alcohol-induced undermining of MR characteristics may well be advisable as routine characterization test
    • Where dictated by therapeutic/considerations (narrow therapeutic index, dire consequences of high Cmax or low Cmin), alcohol sensitive MR formulations should not be approved
clinical consideration of alcohol induced dose dumping11
Clinical Consideration of Alcohol-Induced Dose Dumping
  • Important issue:
    • If a product is a rugged MR drug (i.e., one with an MR mechanism that is resistant to alcohol release), should a generic to that product also be required to use a rugged MR mechanism?
clinical consideration of alcohol induced dose dumping12
Clinical Consideration of Alcohol-Induced Dose Dumping
  • Summary:
    • Through recent regulatory experience, FDA now aware and acting on knowledge that ETOH can undermine some MR products
    • Requires assessment of some current MR products
    • Requires thought as to future regulatory actions/expectations