Clinical Relevance of Alcohol-induced Dose Dumping

1
Clinical Relevance of Alcohol-induced Dose
Dumping

• Robert J. Meyer, MD
• Director, Office of Drug Evaluation II, OND/CDER

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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

3
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

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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

5
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

6
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

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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

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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

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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

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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

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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?

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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