Chiara Piana (1), Shaonan Wang (1), Roberta Bursi (1)
(1) Grunenthal GmbH, Aachen, Germany
Objectives: A modelling and simulation analysis has been performed to evaluate the potential correlation between plasma concentrations and abuse-related effects for a reference drug in comparison with a drug with a high abuse potential profile. The primary endpoint for the abuse-related effects was drug liking “at this moment” measured using a Visual Analogue Scale (VAS).
Methods: Given the distribution of the data, VAS for drug liking “at this moment” was considered as an ordered categorical variable and the scores were binned in three categories (drug disliking, neutral effect, drug liking). A population pharmacokinetics/pharmacodynamics (PK/PD) analysis was performed using a nonlinear mixed-effects approach as implemented in NONMEM 7.2. The final model was selected according to graphical and statistical criteria. After validation of model stability and predictive power, the final PK/PD model was used to predict the mean time-varying probability of drug liking after the administration of hypothetical doses of the reference drug.
Results: A logit model fitted adequately the data and an Emax model best described the correlation between plasma concentrations and drug effect for the reference drug and for the drug with high abuse potential profile. Model-based simulations indicated that in order to reach the same probability of drug liking as the drug with high abuse potential, the reference drug needs dosing higher than the limit of tolerability currently observed.
Conclusions: A novel model-based methodology has been developed to identify a concentration/drug liking correlation and to predict the mean time-varying probability of drug liking after the administration of hypothetical doses of a reference drug. Our investigation shows that modelling and simulation could successfully support the evaluation of abuse potential.
Reference: PAGE 25 (2016) Abstr 5788 [www.page-meeting.org/?abstract=5788]
Poster: Drug/Disease modeling - Other topics