Pharmacokinetics, Tolerability, and Safety of Intranasal Administration of Reformulated OxyContin® Tablets Compared with Original OxyContin® Tablets in Healthy Adults

Abstract

Background and Objective Reformulated OxyContin Ò (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin Ò (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets. Methods This randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18-55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (C max ), time to maximum plasma concentration (t max ), area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration (AUC last ), and area under the plasma concentration-time curve extrapolated to infinity (AUC ? ). The abuse quotient (AQ), calculated as C max /t max , served as an index of the average rate of increase in drug concentration from dosing to t max . Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO 2 ), and electrocardiograms. Results Of 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject's choice. Mean C max values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median t max for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC ? ). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects. Conclusions In contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced C max and increased t max for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC.

Abuse liability of controlled-release oxycodone formulations

“…The area under the concentration-time curve (AUC) was approximated using the linear trapezoidal method. The Cmax/Tmax ratio (abuse quotient) served as an index of the average rate of increase in drug concentration from dosing to Tmax (Perrino et al, 2013). (West, Welch, & Galecki, 2006).…”

“…The only two published studies that have compared the abuse liability of the original OxyContin® and the reformulated OxyContin® are intranasal studies (Perrino et al, 2013;Harris et al, 2013). In these studies, the participants [with a history of opioid abuse/misuse in Perrino et al (2013) and nonmedical use of opioids in Harris et al (2013)], were asked to snort crushed tablets. Together, the studies showed that the original OxyContin® produced relatively greater positive subjective effects, less negative effects (less nasal discomfort) and had a greater abuse quotient (a shorter Tmax and a greater Cmax) compared to the reformulated product.…”

“…Gaps: Only two of these studies (Webster et al, 2012 andPerrino et al, 2013) included pharmacokinetic analysis and positive subjective effects combined. Including pharmacokinetic analysis in abuse liability studies has utility because of its objective nature and the recognized associations between pharmacokinetic data and the positive subjective effects.…”

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.…”

Response to Crudele et al. Commentary on Gudin et al. “Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties”

“…This is not the case for the approved OxyContin label, which contains within a boxed warning the statement “Instruct patients to swallow OXYCONTIN tablets whole; crushing, chewing, or dissolving OXYCONTIN tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone” [4]. Both the Gudin et al 2015 data and Purdue’s own data [5], showing that manipulation of OxyContin was able to compromise its ER mechanism, support inclusion of such a statement in the label.…”