Series Introduction: View all articles in this series.
Regulatory agencies require that any drug (parent or major metabolite) that penetrates the brain and has CNS activity, regardless of its therapeutic indication, be assessed for that drug’s abuse potential. In this series on Assessing Abuse Potential, we are sharing how we design and setup accurate and valid nonclinical GLP abuse liability study types required by regulatory agencies: self-administration, drug discrimination and physical dependency.
Below is a short summary of the full-length article (available for download) that explores how to design a drug discrimination study with in-house data samples from Covance.
About the Drug Discrimination Test
The drug discrimination study assesses a drug’s potential to induce interoceptive stimulus (sensations) comparable to that of another drug. In general, drugs within the same pharmacological class share comparable interoceptive stimulus and are known to substitute for each other in the drug discrimination test.
When evaluating a new drug’s abuse potential, it is important to determine whether the testing drug shares discriminative properties with other known drugs of abuse. If Human Abuse Potential (HAP) studies are required later in the drug development process, information from the drug discrimination study may be used to determine the drug class experience required by the recreational drug user population selected for the study.
A Typical Study Design for Drug Discrimination
Drug abuse liability studies should be conducted to GLP.
Each drug discrimination study includes the following phases:
- The lever-pressing phase in which rats are trained to lever press for a reward (i.e., sucrose pellets).
- The double alternation discrimination phase in which the rats are trained to discriminate between a “drug” lever and a “no-drug” lever in response to a discriminative stimulus. The training regimen is such that the training drug is administered on 2 consecutive days, followed by no drug on 2 consecutive days, and so on.
- The single alternation discrimination phase is similar to the previous phase, but it provides heightened difficulty as testing between drug and no drug (e.g. saline) is alternated daily.
- The pre-testing phase (final stage of test training) to verify that the rat responds as anticipated under test conditions when dosed with the training drug or no drug (e.g. saline).
- First test session in which a dose response curve is obtained for the training drug.
- Final test session in which a dose response curve is obtained for the test drug.
Selecting the Training Drug
The training drug should be in the same pharmacological class as the test drug whenever possible, and should be scheduled under the Controlled Substance Act.
For a test drug with a novel mechanism of action, a training drug that has a similar therapeutic indication or behavioral profile may be proposed. In some instances, multiple training drugs may be required or the test article itself may be used as the “training drug.”
Analyzing the Data
The following parameters should be evaluated:
The percentage of lever presses on the drug-associated lever.
If the drug-associated lever is pressed . . .
- More than 80% = Full Generalization
- Between 20 and 80% = Partial Generalization
- Fewer than 20% = Vehicle Appropriate Responding
The FDA guidance states that “if the test drug produces full or partial generalization to the training drug (a known drug of abuse), it may have abuse potential.”
The Lever-Pressing Response Rate
The percentage of correct lever presses must be viewed in conjunction with the lever pressing response rate. Severe impairment of lever-pressing ability raises concerns about a test result’s reliability. Datasets in this article will demonstrate the impact of this.
Lever Identification Selected to Provide First Reward
The identity of the first lever selected to provide a reward is an indication of the rat’s initial response to the discriminative cue.
It typically takes 22 weeks to complete the in-life phase of the drug discrimination test.
Stimulants, Opioids, Sedatives, Hallucinogen and Cannabinoid Examples
The final portion of the article explores the interpretation of in-house data, related to stimulants(amphetamine & cocaine); opioids (morphine, buprenorphine, methadone); benzodiazepines/sedatives (phenobarbital, pentobarbital, midazolam), hallucinogens (ketamine, PCP) and cannabinoids.
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