A translational pharmacology approach to understanding the predictive value of abuse potential assessments

Abstract

Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk. To address this, we analyzed data from 100 small molecules to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package. These models range from the assessment of in-vitro binding and functional profiles at receptors or transporters typically associated with abuse through in-vivo models including locomotor activity, drug discrimination, and self-administration in rodents. Data from subjective report assessments in humans following acute dosing of compounds were also included. The predictive value of each model was then evaluated relative to the scheduling status of each drug in the USA. In recognition of the fact that drug scheduling can be influenced by factors other than the pharmacology of the drug, we also evaluated the predictive value of each assay for the outcome of the human subjective effects assessment. This approach provides an objective and statistical assessment of the predictive value of many of the models typically applied within the pharmaceutical industry to evaluate abuse potential risk. In addition, the impact of combining information from multiple models was examined. This analysis adds to our understanding of the predictive value of each model, allows us to critically evaluate the benefits and limitations of each model, and provides a method for identifying opportunities for improving our assessment and prediction of abuse liability risk in the future.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Subsequent studies determined that laboratory animals would self-administer most drugs abused by humans and would not self-administer many other drugs not abused by humans (Thompson and Schuster, 1964;Deneau et al, 1969;Johanson and Balster, 1978;O'Connor et al, 2011). These findings provided evidence for the sensitivity and selectivity of preclinical drug selfadministration procedures to detect drug effects related to abuse potential in humans, and drug self-administration procedures have subsequently emerged as key tools for abuse potential assessment (Ator and Griffiths, 2003;Carter and Griffiths, 2009;Horton et al, 2013).…”

“…9B for a series of monoamine releasers, and there was a significant correlation between measures of drug-induced facilitation of ICSS in rats and of reinforcing efficacy in a progressive-ratio procedure in rhesus monkeys. One implication of this correlation is that ICSS might be useful not only for predicting presence or absence of reinforcing effects but also for stratifying those effects along a continuum of reinforcing strength for monoamine releasers (Brady and Griffiths, 1976;Richardson and Roberts, 1996;Horton et al, 2013). Table 6 presents a more qualitative comparison of results in ICSS and drug self-administration procedures for representative drugs discussed in this review article.…”

“…For decades, drug self-administration procedures have been a standard in preclinical abuse potential testing, and results obtained with these procedures have been reviewed extensively (Ator and Griffiths, 2003;Carter and Griffiths, 2009;O'Connor et al, 2011;Horton et al, 2013). Accordingly, one measure of the utility of ICSS in abuse potential testing is the comparison of results obtained with ICSS and drug selfadministration procedures.…”

“…13B shows that caffeine also facilitated ICSS in rats responding under a frequency-rate procedure (M. Lazenka and S. S. Negus, unpublished observations). A recent review of the drug self-administration literature concluded that caffeine does not produce reinforcing effects in preclinical drug self-administration studies (Horton et al, 2013), although other investigators have concluded that caffeine may maintain self-administration under a limited range of conditions (Griffiths and Woodson, 1988). Overall, both ICSS and drug self-administration procedures agree that abuse-related effects of caffeine are weak; however, in the context of the present review, caffeine is the only drug that appears to produce more robust evidence for abuse potential in ICSS than in drug self-administration procedures.…”

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

“…We investigated the abuse liability profile of three pyrovalerone analogs that were recently emergency scheduled by the Drug Enforcement Administration: 4ʹ-MePPP, a-PBP, and a-PVP. Locomotor activity (test for psychostimulant effects), drug discrimination (test for discriminative stimulus effects), and conditioned place preference (test for reward-like effects) assays are commonly used for predicting the abuse potential of drugs (Carter and Griffiths, 2009;Horton et al, 2013).…”