Abuse Liability Screening in Animals

Abuse Liability Screening in Animals

Understanding FDA Mandated Animal Behavioral Pharmacology Screening

Paul J. Kruzich, Ph.D.Principal ConsultantPreclinical Consulting Services, LLCwww.preclinicalconsultingservices.com

Some General Backgroundfor the FDA Guidance

Preclinical Consulting Services, LLC

What is “Abuse Potential?”

Abuse potential *when a drug is used in nonmedical situations, repeatedly or even sporadically, for the positive psychoactive effects it produces, it is characterized as “abuse potential”.

*Draft Guidance for Industry Assessment of Abuse Potential of Drugs prepared by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf



Common Characteristics of Abused Drugs*

Central nervous system (CNS) activity, including:sedationeuphoria perceptual and other cognitive distortionshallucinations mood changes

Drugs with abuse potential often (but not always) produce psychic or physical dependence and may lead to the disorder of addiction.

*Excerpted from Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970), reprinted in 1970 U.S.C.C.A.N. 4566, 4603.


http://www.justice.gov/dea/pubs/csa.html

How does the FDA Classify Drugs as “Abuse Liable?”


Under 21 U.S.C. 811(b) of the Controlled Substances Act (CSA), the Secretary of Health and Human Services is required to consider, in a scientific and medical evaluation, 8 factors determinative of control under the CSA.

Following consideration of the 8 factors, the Secretary must make 3 findings and a recommendation for scheduling a substance in the CSA.


Excerpted from the Draft Guidance for Industry Assessment of Abuse Potential of Drugs

Factors Leading to Labeling a Drug“Abuse Liable”



The 8 factors of 21 U.S.C. 811(c)

1. The drug’s actual or relative potential for abuse

2. Scientific evidence of the drug's

pharmacological effects

3. The state of current scientific knowledge

regarding the drug or similar substances (e.g.,

class/mechanism of action)

4. The drug’s history and current pattern of abuse





The 8 factors (cont.)5. The scope, duration, and significance of

abuse

6. What, if any, risk there is to the public health

7. The drug’s psychic or physiological dependence liability

8. Whether the substance is an immediate precursor of a substance already controlled.





A Sponsor’s MandateIf the drug has a potential for abuse, the

sponsor must submit “a description and analysis of studies or information related to abuse of the drug, including a proposal for scheduling, under the Controlled Substances Act.” (21 CFR 314.50(d)(5)(vii)).

A description must be submitted “of any studies related to overdosage, etc. including information on antidotes, or other treatments, if known” (id.) in the new drug application (NDA).

Preclinical Consulting Services, LLCExcerpted from the Draft Guidance for Industry Assessment of Abuse Potential of Drugs


When Should an Abuse Potential Assessment Be Submitted to FDA?

A sponsor must submit in the NDA an assessment of studies and other information related to the potential abuse of a drug when:the drug affects the central nervous system

(CNS) the drug is chemically or pharmacologically

similar to other abused drugsthe new drug produces psychoactive effects

such as sedation, euphoria, and mood changes.




An assessment of abuse potential may be needed for new (novel) drugs, including new molecular entities (NME).

For a marketed drug product that presents an unexpected adverse event profile that includes events that are related to abuse potential or that is being re-evaluated for a new route of administration that could affect the abuse potential of the drug.

When Should an Abuse Potential Assessment be Submitted to FDA? (cont.)




What Should be Included in an Abuse Potential Submission?

A summary, interpretation, and discussion of abuse potential data provided in the NDA

A proposal and rationale for placing (or not placing) a drug into a particular schedule of the Controlled Substances Act


What Should Be Included in an Abuse Potential Submission? (cont.)

All primary data related to the abuse potential characterization of the drug, organized under the following subheadings: ChemistryPreclinical Pharmacology Animal Behavioral and Dependence Pharmacology Pharmacokinetics/Pharmacodynamics Human Abuse Potential Laboratory Studies Clinical Trial Data Relative to Abuse and Dependence

Potential Integrated Summaries of Safety and Efficacy Foreign Experience with the Drug (Adverse Events,

Abuse Potential, Marketing, and Labeling)

Preclinical Consulting Services, LLCExcerpted from the Draft Guidance for Industry Assessment of Abuse Potential of Drugs


What Should Be Included in an Abuse Potential Submission? (cont.)

All primary data related to the abuse potential characterization of the drug, organized under the following subheadings: ChemistryPreclinical Pharmacology Animal Behavioral and Dependence Pharmacology Pharmacokinetics/Pharmacodynamics Human Abuse Potential Laboratory Studies Clinical Trial Data Relative to Abuse and Dependence

Potential Integrated Summaries of Safety and Efficacy Foreign Experience with the Drug (Adverse Events, Abuse

Potential, Marketing and Labeling) Preclinical Consulting Services, LLC

Animal Abuse Liability Screening!

Animal Behavioral Pharmacology for Abuse Screening

Drug Discrimination

Self-administration


Drug Discrimination

Provides a behavioral indication of a drug’s pharmacological mechanism of action in an intact animal (usually rats or nonhuman primates)

It does not specifically provide an index of whether or not a drug will be abused. Rather, it provides an indication of whether or not it’s pharmacological actions are similar to other “reference” abused drugsSee Carter and Griffiths 2009 and Mansback et al 2003

for excellent reviews


Drug Discrimination Procedures Animals are trained to discriminate between a reference drug that creates

a change in internal state (e.g., amphetamine—the reference drug should have a similar mechanism of action or chemistry as the novel compound) and an inert vehicle (e.g., saline) in an operant task “Motivated” (food or water restricted) animals are trained to press levers to

receive a “reward” (a tasty food pellet or fruit juice) A computer tracks the number of responses made and rewards earned

Following lever training, animals are then administered the reference drug and trained to press “Lever A” in order to receive a reward—several rewards can be earned during a session Responding of “Lever B” (saline) results in no reward

The next session/day animals are administered an inert vehicle and trained to press “Lever B” in an operant chamber in order to receive a reward Pressing “Lever A” on a saline day results in no reward


A Standard Drug Discrimination Apparatus

ResponseLever

Food Hopper

RatHere

Adapted from Med Associates © Copyright Med Associates Inc., 1998-2011. All Rights Reserved—Preclinical Consulting Services has no association with Med Associates


Depiction of Inside wall of Drug Discrimination (operant) Chamber (what the animal sees)

SalineLever B

DrugLever A

Food pellet rewardin dispenser dish

Pellet Dispenser

Tube

Pellet being dropped from dispenser/hopper into dish


Drug Discrimination Procedures (cont.)

Over days, the number of accurate lever presses necessary to receive the “reward” is increased to ensure accuracy The animal administered the reference drug must

press Lever A 10 times in a row and avoid pressing Lever B during the 10 consecutive responses The increased requirement serves as an index of

specificity/accuracy

Once the animal has demonstrated accurate discrimination between the reference drug and saline, testing is initiated with the novel compound.


During testing, the animal is administered the novel compound

Based on its response pattern, the animal “tells” the researcher whether the novel compound is similar to the reference compound or inert vehicle (there is no “correct” or “incorrect” response).

The animal does this by responding on the “drug” or “vehicle” lever—either lever will deliver a reward during a “test” session.

If the novel compound induces a similar internal “cue” or interoceptive effect that is similar to the reference drug (the animal responds on the “drug” lever) the novel compound must be considered “abuse liable.”

Drug Discrimination Procedures (cont.)


Self-AdministrationRodents and nonhuman primates will self-

administer most drugs of abuse that humans self-administer (see O'Connor et al 2011 for excellent review)

Animals (typically rats, occasionally nonhuman primates) are implanted with indwelling intravenous catheters


A Typical Rodent Drug Self-administration Chamber Setup

Adapted from Med Associates © Copyright Med Associates Inc., 1998-2011. All Rights Reserved—Preclinical Consulting Services has no association with Med Associates

InfusionSyringe

Catheter InfusionLine

Response Lever

RatHere


StimulusLight

Depiction of Inside wall of self-administration(operant) chamber (what the animal sees)

DrugLever


Stimulus Light(to signal when an infusion is occurring)

Self-Administration (cont.)

Through behavioral techniques, animals are trained to self-administer (lever press/remotely administer) several intravenous infusions of a reference drug of abuse (e.g., amphetamine) during daily sessions The number of allowable infusions (to protect from overdose,

self-administered infusions are controlled and recorded by a computer)

The reference drug should be in the same class or have a similar mechanism of action as the novel compound (based on established pharmacology and chemistry)


Self-administration (cont.) Once the animal is reliably self-administering the reference drug (based

on established criteria), the reference drug is removed from the infusion syringes and replaced with saline the next day

Animals will not self-administer saline After a day of saline access, the animals are given access to the

training drug again the next day

After several alternating daily reference drug/saline sessions, very reliable and robust patterns of behavior will occur:

When the syringe is loaded with the reference drug, animals will show good response for drug (e.g., make several [hundred] responses for drug)

When the syringe is loaded with saline, the animal will almost immediately stop responding within the first minutes of a daily saline/vehicle session (animals make significantly fewer responses compared to drug days)


Once reliable patterns of behavior are established, a dose response curve is generated for the reference drugAnimals typically compensate for lower doses by

self-administering more infusions; doses higher than the training doses are self-administered, but fewer administrations are taken per session This dose-response pattern has been describe as an

“inverted U” (Koob 2003)If the dose is too low, experienced animals will not

self-administer that particular dose, much like saline

Self-administration (cont.)


Once the complete dose response curve of the reference drug is generated, novel compound screening occurs:Different doses of the novel compound are provided

to animals on “test” days

Test days are interspersed between normal reference drug and saline days

If the experimental animal self-administers the novel compound based on a previously determined set of criteria, the compound is considered “abuse liable.”

Self-administration (cont.)


Bibliography1. American Academy of Pain Medicine, American Pain Society and American Society of

Addiction Medicine Consensus Document. Definitions related to the use of opioids for the treatment of pain, 2001. http//www.painmed.org/pdf/definition.pdf.

2. Carter LP, Griffiths RR. Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend. 2009 Dec 1;105 Suppl 1:S14-25 . (http://bit.ly/fK1d0y)

3. Controlled Substances Act (CSA), as amended February 15, 1996 (21 U.S.C. 801 et seq.). (http://www.justice.gov/dea/pubs/ csa.html)

4. Draft Guidance for Industry Assessment of Abuse Potential of Drugs prepared by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf)

5. Koob GF (2003) Drug Reward and Addiction. In Fundamental Neuroscience (2nd Ed) Academic Press; San Diego, CA

6. Mansbach RS, Feltner DE, Gold LH, Schnoll SH. Incorporating the assessment of abuse liability into the drug discovery and development process. Drug Alcohol Depend. 2003;70:S73–85 . (http://bit.ly/gHo0uV)

7. O'Connor EC, Chapman K, Butler P, Mead AN. The predictive validity of the rat self-administration model for abuse liability. Neurosci Biobehav Rev. 2011;35(3):912-38. (http://dx.doi.org/10.1016/j.neubiorev.2010.10.012)


http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T63-4W91CM2-B&_user=10&_coverDate=12/01/2009&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1646107306&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=65bd77c2bc4eb948917ae2a3d74d7a52&searchtype=a





http://bit.ly/gHo0uV

http://dx.doi.org/10.1016/j.neubiorev.2010.10.012




Contact Information

Paul J. Kruzich, Ph.D.Principal ConsultantPreclinical Consulting Services, LLCpaul.kruzich@preclinicalconsultingservices.comwww.preclinicalconsultingservices.com

mailto:[email protected]

mailto:[email protected]

http://www.preclinicalconsultingservices.com/

Accompanying Commentary at:

ToxInsights

Toxicological Insights for the Global Pharmaceutical

Community

http://www.tigertox.com/2011/04/18/drug-

abuse-liability-testing/

Health & Medicine

Abuse Liability Screening in Animals