A Randomized, Double-Blind, Double-Dummy Study to Evaluate the Intranasal Human Abuse Potential and Pharmacokinetics of a Novel Extended-Release Abuse-Deterrent Formulation of Oxycodone

Abstract

Objective. Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein “DETERx”).Design. Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study.Setting. Clinical research site.Subjects. There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods.Methods. The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx—administered as either a crushed intranasal (IN) or an intact oral (PO) preparation—with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control.Results. For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated.Conclusions. Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.

The Comparative Pharmacokinetics of Physical Manipulation by Crushing of Xtampza ® ER Compared with OxyContin ®

“…Data from in vitro studies have demonstrated that the formulation is difficult to prepare for injection [9]. Data from the combination of in vitro and in vivo studies have shown that it is difficult to reduce the particle size of Xtampza ER microspheres [8], the ER characteristics are maintained after manipulation [10], and that Xtampza ER has lower drug liking after chewing [29] and after intranasal administration [30] when compared with IR oxycodone.…”

Oxycodone DETERx®: A Novel Abuse-Deterrent, Extended-Release Analgesic Option for the Treatment of Patients with Chronic Pain

“…The pharmacokinetic profile of intranasally administered crushed oxycodone DETERx was assessed in nondependent subjects. Intranasal administration of crushed oxycodone DETERx did not result in higher peak plasma concentrations than did orally administered oxycodone DETERx, unlike that of intranasal administration of crushed IR oxycodone, which produced as much as twice the oxycodone C max (Table 2) [26]. The time to peak concentration was the same for both intranasal and oral administration of oxycodone DETERx [26], indicating that intranasal administration of oxycodone DETERx does not provide rapid increases in plasma concentrations (i.e., central exposure to oxycodone).…”

“…The intranasal abuse potential of oxycodone DETERx was assessed in a (category 3) randomized, double-blind, positive- and placebo-controlled crossover study [26]. The four treatments included oxycodone DETERx administered as either an intact oral capsule or a crushed intranasal preparation, IR oxycodone administered intranasally, and placebo.…”

“…5Percent reduction of drug liking visual analog scale ( E max ) for crushed oxycodone DETERx vs. crushed immediate-release oxycodone after intranasal administration. Adapted with permission from [26] …”

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended‐Release Tablets

“…3,4 Support for this relationship has been demonstrated in studies of opioids, sedatives, and methylphenidate. [4][5][6][7][8] However, at the individual subject level, PK/PD correlations are often much weaker, suggesting that PK/PD relationships are highly variable and may depend on factors such as formulation or route of administration. 9,10 An extended-release (ER) tablet formulation of hydrocodone (Vantrela R ER; Teva Pharmaceuticals, Inc., Frazer, Pennsylvania) was developed using the CIMA R Abuse-Deterrence Technology platform to provide resistance against the rapid release of hydrocodone when tablets are manipulated or taken with alcohol.…”