Preclinical Challenges for Assessing Abuse Potential of Nontraditional Drugs and Drug Formulations

1. Preclinical Challenges for Assessing Abuse Potential of Nontraditional Drugs and Drug Formulations Nancy A. Ator Division of Behavioral Biology Department of Psychiatry and Behavioral Sciences Johns Hopkins School of Medicine

2. Definition of “Abuse Liability”adapted from FDA Draft Guidelines,1998 • The likelihood that a drug with anabolic, psychoactive or CNS effects will sustain patterns of non-medical self-administration that result in disruptive or undesirable consequences. • “Abuse liability may be described for regulatory purposes by variations in either the likelihood and severity of self-administration or the likelihood and severity of undesirable consequences.”

3. Definition of “Abuse Potential”/“Abuse Liability”adapted from FDA Draft Guidelines, 2010 • The probability that a drug will be used in non-medical situations repeatedly, or even sporadically, for the positive psychoactive effects it produces. Drugs characterized by their CNS activity. • Examples of psychoactive effects produced: sedation, euphoria, perceptual and other cognitive distortions, hallucinations, and mood changes. • Such drugs often (but not always) produce psychic or physical dependence and may lead to the disorder of addiction.

4. Definition of “Addiction” (newly added in 2010 FDA Draft Guidelines) • Chronic neurobiological disorder with genetic, psychosocial, and environmental aspects, characterized by one or more of the following: • IMPAIRED CONTROL OVER DRUG USE • COMPULSIVE USE • CONTINUED USE DESPITE HARM • CRAVING

5. Preclinical Behavioral Pharmacology (per 1998 Draft guidance) FunctionAssessment • Reinforcing effects : Self-administration • Discriminative effects : Drug discrimination • Physical dependence : Effects of abrupt abstinence • Tolerance : Effects of chronic dosing

6. Animal Behavioral Pharmacology Studies(adapted from FDA Draft Guidelines, 2010) Assessment Method • Rewarding properties : Self-administration (or Conditioned Place Preference?) • Perceptions* : Drug discrimination • Dependence potential : Withdrawal syndrome (+ tolerance determination) • Motor functioning : Psychomotor tests *Psychic or Physical

7. Self-administration via the Intravenous Route“Gold Standard” for assessing a drug as reinforcer • Rationale: Early research showed that animals self administer the same drugs that humans abuse with few exceptions. • Value: Assesses drug’s ability to maintain drug taking per se compared to the non-drug (vehicle) control. • Valuable characteristic of intravenous delivery • The speed of getting to the target receptor--speed of effect

8. Self-administration via the IV Route: Alternatives? • Oral Self-administration? • The good correspondence with human abuse has not been established across a wide range of drug classes as has occurred with IV studies • Often can be more time consuming than IV studies • Intragastric Self-administration? • Attempts to use this route in non-human primates have been largely unsuccessful (lack of buccal absorption may be a problem) • What about Conditioned Place Preference? • Not a measure of drug taking behavior • Not validated in terms of good correspondence with human drug abuse

9. IV Self-administration: “Standard” Procedure • Fixed number of responses required for each self-injection • Timeout before opportunity for next injection • Choice of duration can permit manipulation of drug accumulation • Use of a quickly-eliminated positive control drug as baseline • Permits substitution of each test condition into a constant context • Improves efficiency of evaluation • Use of relatively fixed number of sessions at each test dose • Period needs to be long enough to permit transition from baseline • Too short a period could result in false positives or negatives

11. Drug Discrimination: Animal model of “subjective” effects • An “Expert” compares test drugs to his “Standard,” reporting whether the test drug is like/unlike the standard. Similar to situations in which a drug user would be asked to say whether a novel drug’s subjective effects are like those of a familiar drug. • Great pharmacological and neuropharmacological specificity, depending on the selectivity of the drug used to train the discrimination. Thus, usefulness in abuse liability testing is critically dependent on the training condition for results to be relevant.

12. Drug Discrimination: Methodological Considerations • Choice of training drug and dose • Route of administration • Choice of pretreatment time--may need time course study • Choice of criterion for accuracy in performance prior to testing • Spacing of test sessions, and training sessions after test drug, depending on drug half-life and active metabolites

13. Selectivity in Drug Discrimination Test Profiles

15. Physical Dependence Assessments Chronic delivery of drug for some period of time to determine whether abrupt withdrawal of the drug results in signs indicating that physiological dependence had developed. • Useful for studying the effects of chronic drug per se on normal behavior • Useful for determining if tolerance develops to drug effects • Useful for characterizing the nature of the withdrawal syndrome • Signs and symptoms • Severity • Duration

16. Physical Dependence Assessments Important Design Considerations • Nature and timing of assessments to be made throughout • Assessments during drug delivery can track tolerance development • Control condition: Vehicle delivery • Drug Dosing Conditions: Strong test • Dose: Rationale for choice should include clear behavioral effects • Route: Planned route for clinical use? • Frequency of dosing: Consider half-life • Duration: Best may be shorter duration of high dose • Withdrawal: Spontaneous best to characterize syndrome & severity • Daily assessments to reveal onset of signs and the time-course of resolution • Assessment in relation to both vehicle and drug delivery conditions

17. Withdrawal Signs in the First 15 Days after Chronic Drug Delivery Ended

18. Reduced Abuse Liability Baboon – Withdrawal Ator et al, 2010

19. Over-arching Methodological considerations for Preclinical Abuse Liability Assessments • Choosing Doses and Dose Ranges • Positive and Negative Controls • Use of Multiple Dependent Measures • Experimental Designs • Choice of Species

20. Considerations in Choices of Doses & Dose Ranges • Extrapolate from preliminary data on behavioral effects in other animals to choose a starting dose. • Dose range for Self-administration and Drug Discrimination need to be determined empirically based on results as study progresses. Dose increments as well. • Use of target blood levels extrapolated from humans may lead to incomplete evaluation.--Need to aim for maximum tolerable dose to assure complete characterization.

21. Controls • Negative: • Test drug vehicle • Compound that shows up negative in the assay IF there is concern that the assay does not differentiate among drugs. Previous data from the laboratory can be useful here. • Positive: • Pharmacologically similar compound (preferably used for same indication) • Known to have abuse liability • Shows up positive in the assay

22. Use of Multiple Dependent Measures • Trained Operant behavior • Untrained behavior: Particularly in Dependence Studies, but also Self-administration • Planned observations of natural behavior and appearance (e.g., locomotion, feeding, grooming, etc.) • Performance of simple tasks • Weights • Blood levels • Important if drug’s effects are negative in a study

23. Experimental Designs • Single Subject Designs: Work well with non-human primate studies • Permits greater flexibility in adjusting parameters with novel compounds for greater efficiency in assessment • Each subject is own control; within-subject replication can assess reliability; across-subject replication determines generality • Fewer total subjects may be needed • Within-Subject Group Design • Can be problematic if animals are catheterized • Randomization of doses may be difficult without pilot data • Performance of simple tasks • Between-Subject Group Designs • May be best for rats

24. Considerations for Choice of Species: Rat or Non-human Primate? • Relevant receptor systems? • Drug metabolism • Active metabolites? • Ability to characterize nature of withdrawal syndrome with relevance to humans may be greater in monkeys • Pharmacokinetic studies have shown better prediction of human pharmacokinetics from monkey than from rat and dog (Ward & Smith, 2004; Ward et al., 2005), which has implications for drug action and time-course in abuse liability assessments of novel compounds as well.

25. Challenges for Preclinical Abuse Liability Assessment? • New receptor targets not associated with currently controlled substances • A problem for Drug Discrimination: Choice of training drug(s) • New formulations designed to prevent tampering: Focus is on assessment of the substance itself; formulation can mitigate abuse potential. • Prodrugs: Having long intervals between Self-Injections could be useful. Do time course assessments in Drug Discrimination. • Drug combinations--Use multiple Drug Discrimination training conditions • Solubility--Can be a challenge for Self-Injection. Manipulate volume of delivery for test drug and control conditions.

26. Good Laboratory Practice Regulations & Abuse Liability Assessments Draft FDA Guidance has long urged adherence to the “Principles” of the GLPs. Clarity is needed regarding call for full consistency with GLPs. • The documentation and record-keeping for experimental procedures are generally consistent with good scientific practices. • Some elements of GLPs are not relevant to studies in which animals will not be sacrificed for analysis of organs/tissues. • These studies are best viewed as characterizations of the pharmacology of the drug rather than its toxicology. • These types of behavioral studies require flexibility in manipulating parameters for individual subjects as a matter of course.

27. Eight-Factor Analysis for Control of a Drug under the CSA Required Under CSA, 21 USC 811(c) • Its actual or relative potential for abuse • Scientific evidence of its pharmacological effects • The state of current scientific knowledge regarding the drug • Its history and current pattern of abuse • The scope, duration, and significance of abuse • What, if any, risk there is to the public health • Its psychic or physiological dependence liability • Whether it is an immediate precursor of a controlled substance