Bioequivalence of oxymorphone extended release and crush-resistant oxymorphone extended release

Abstract

Background

A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release (Oxy-ER) and a crush-resistant formulation of oxymorphone extended-release (Oxy-CRF).

Methods

In three open-label, randomized studies, healthy adults at a clinical research center received two single oral doses of Oxy-ER and two single doses of Oxy-CRF, each separated by a ≥7-day washout. Doses were administered under fasted conditions (study 1, 5 mg doses; study 2, 40 mg doses) or after a high-fat breakfast (study 3, 40 mg doses). Subjects administered 40 mg doses also received naltrexone. The primary endpoint was systemic oxymorphone exposure; the bioequivalence criterion was met if the 90% confidence intervals of the geometric mean ratio (Oxy-CRF/Oxy-ER) for oxymorphone area under the curve from time 0 to the last measured concentration (AUC_0–t), AUC from time 0 to infinity (AUC_0–inf), and maximum plasma concentration (C_max) were within 0.8–1.25. Safety was assessed by monitoring adverse events.

Results

In studies 1, 2, and 3, the safety population comprised 30, 37, and 36 subjects and the pharmacokinetics population comprised 27, 30, and 29 subjects, respectively. Oxy-ER and Oxy-CRF produced similar mean ± standard deviation oxymorphone AUC_0–t (study 1, 5.05 ± 1.55 versus 5.29 ± 1.52 ng · h/mL; study 2, 31.51 ± 10.95 versus 31.23 ± 10.33 ng · h/mL; study 3, 50.16 ± 14.91 versus 49.01 ± 14.03 ng · h/mL) and C_max (0.38 ± 0.11 versus 0.37 ± 0.12 ng/mL; 2.37 ± 1.20 versus 2.41 ± 0.94 ng/mL; 5.87 ± 1.99 versus 5.63 ± 2.26 ng/mL) under all conditions. The 90% confidence intervals for plasma oxymorphone AUC_0–t, AUC_0–inf, and C_max fulfilled the bioequivalence criterion. Adverse event rates were similar with Oxy-ER and Oxy-CRF (study 1, 25% versus 23%; study 2, 9% versus 16%; study 3, 20% each group).

Conclusion

Oxy-CRF and Oxy-ER (5 mg and 40 mg) are bioequivalent under fasted and fed conditions, suggesting that Oxy-CRF will have clinical efficacy and safety equivalent to Oxy-ER.

Keywords:

• abuse deterrent
• bioequivalence
• opioid
• oxymorphone
• pharmacokinetics
• substance abuse

Acknowledgments

The Crush Resistant Formulation technology was developed by and is property of Gruenenthal, Aachen, Germany. Endo holds an exclusive license for the use of the technology with Opana ER.

Axel Juan and Audrey Martinez, both of SeaView Research Inc (Miami, FL) were principal investigators for these studies. Clinical monitoring of the studies was performed by Paula Allen. Bioanalytical analyses were performed at Cetero Research (Houston, TX).

Editorial Support (literature search, document retrieval, medical writing, and copy editing) for the development of this manuscript was provided by Nicole Strangman, PhD, and Robert Gatley, MD, of Complete Healthcare Communications, Inc (Chadds Ford, PA) with funding from Endo Pharmaceuticals Inc (Chadds Ford, PA).

Disclosure

All authors were employees of Endo Pharmaceuticals Inc during the course of these studies. Endo Pharmaceuticals Inc (Chadds Ford, PA) provided funding for the study and manuscript development.