# Presentation: 055513

## 
FDA Open Public Hearing
May 5, 2008

Beatrice Setnik, PhD
Director, Scientific Business Development
DecisionLine Clinical Research Corporation
Toronto, Ontario, Canada

Disclaimer:
DecisionLine provides consulting services and conducts clinical trials to assess abuse liability, drug interactions and tamperability for CNS active drugs.

**FDA Open Public Hearing**
**May 5, 2008**
**Beatrice Setnik, PhD**
- Director, Scientific Business Development
- DecisionLine Clinical Research Corporation
- Toronto, Ontario, Canada
***Disclaimer:***
- DecisionLine provides consulting services and conducts clinical trials to assess abuse liability, drug interactions and tamperability for CNS active drugs.

## Alcohol and “Dose Dumping”

**The term “dose dumping” is frequently used and often indiscriminately:**
- Describes accelerated drug release from modified release  formulations (MRF)
- The term is non-quantitative and implies actual clinical importance
- Based historically on PK data; for most CNS drugs PK is highly variable and there is a poor correlation of PK and PD
**Pharmacokinetic (PK) data do not predict**
- Safety – individual or risk to groups of patients
- Pharmacodynamic effects e.g. motor or cognitive impairment
- Efficacy
**Naltrexone “cover” often used with opioids (e.g. Palladone****TM**** study)**
- Statistically significant increase in mean plasma morphine levels (AUC0-24 ↑ 23%; Cmax ↑14.5%) resulting from co-administration of morphine (60 mg) + naltrexone (300 mg) (Bashaw et al., 1995)
- Prevents gathering data on safety and PD data
**The clinical importance can only be determined if pharmacodynamic and safety measures are included**** **
- Relevance to patient populations _and_ drug abusers

## Correlation of In Vitro and Clinical Data – Alcohol effects

- In vitro data not always correlated to clinical data:
**e.g. OPANA® ER**
- In vitro data showed that oxymorphone was not released more rapidly in 500 mL of 0.1N HCl solutions containing ethanol (4%, 20%, and 40%)
- Clinical data combining 40 mg OPANA® ER and alcohol (4%, 20% and 40%) in healthy, fasted volunteers showed that with 40% ethanol:
- Mean AUC (oxymorphone) was 13% higher (not statistically significant)
- Cmax was highly variable, increased on average by 70% and up to 270% in individual subjects
- In vitro studies:
- Inexpensive, quick
- Provide data on physical/chemical properties of formulation
- However, clinical studies:
- Provide valuable information on pharmacokinetics and pharmacodynamic effects when various doses of alcohol are administered at various time, in relation to drug administration

## Terminology

- “Abuse deterrent” and “tamper resistant” are often interchanged; they are not equivalent.
- “Tamper Resistant” formulations can either:
- Contain a controlled release caption that is not easily accessible
- Difficult to crush/chew/grind/dissolve
- Or when tampered with have physical/chemical properties that are not appealing for administration
- Prevention of snorting, injection, smoking, oral administration
- Addition of aversive/blocking agents (e.g. capsaicin)
- _However_, may contain an IR caption that may be abused when intact
- “Abuse Deterrent” formulations
- Means the formulation is designed without tampering to be less attractive for non-medicinal use, e.g. by decreasing the peak high, delaying the time of the peak effects or the rate of onset of effects or decreasing the overall effects (AUC)
- _But_ in order to be effective, cannot be easily defeated

## Summary

- Experimental human studies and epidemiologic safety data are needed to address the clinical relevance of drug/alcohol interactions and “dose dumping”.
- Determination of clinical importance requires the inclusion of sensitive clinical measures of safety and pharmacodynamic endpoints in pharmacokinetic studies
- “Dose dumping” should only be used to describe situations where tampering results in a clinically important consequence
- Criteria for clinical importance should be developed for target drug classes
- Appropriate terminology and evidence is required to describe new formulation technologies designed to reduce tampering and abuse potential.