(238) The relationship between the pharmacokinetics of morphine abuse-deterrent, extended-release, injection-molded tablets and pharmacodynamic outcomes in oral and intranasal human abuse potential studies

Abstract

It is generally accepted that rapid drug absorption and high plasma concentrations contribute to opioid abuse potential; however, few studies have evaluated this relationship. The US FDA has stated that the correlation between pharmacokinetics (PK) results and pharmacodynamics (PD) outcomes in abuse-deterrent (AD) opioid studies needs additional research. Herein, we examined the PK/PD relationships of morphine AD, extended-release (ER), injection-molded tablets (morphine-ADER-IMT; Egalet Corporation, Wayne, PA) and other treatments in two single-center, double-blind crossover human abuse potential studies in volunteers who were nondependent, recreational opioid users. In the oral study, subjects received 60 mg of intact morphine-ADER-IMT, manipulated morphine-ADER-IMT, crushed morphine ER, and placebo. In the intranasal study, subjects received 60 mg of manipulated intranasal high-volume morphine-ADER-IMT, manipulated intranasal low-volume morphine-ADER-IMT, crushed intranasal low-volume morphine ER, oral intact morphine-ADER-IMT, and placebo. The relationships between the PK parameters of peak plasma concentration (Cmax), time to Cmax (tmax), and abuse quotient (AQ; Cmax/tmax) and the PD abuse potential outcomes of at-the-moment Drug Liking peak effect (Emax), and Overall Drug Liking and Take Drug Again at 12 hours Visual Analog Scale scores were evaluated. The 10-unit slope, the predicted change in a PD outcome for a 10-unit change in the PK parameter, was determined for each PK/PD association. All PK parameters were significantly associated with all PD measures (P≤0.02) except between tmax and Take Drug Again in the intranasal study (P=0.12). Abuse potential measures were positively associated with Cmax and AQ and negatively associated with tmax. PK parameters were most effective in predicting Drug Liking Emax, followed by Overall Drug Liking and Take Drug Again. Cmax was numerically a slightly better predictor than AQ. The model may have potential predictive value for other AD products in development and advance the understanding of this important relationship for AD opioid development. Funded by Egalet Corporation.