Bioequivalence of oxymorphone extended release and crush-resistant oxymorphone extended release
Irma H Benedek, Janet Jobes, Qinfang Xiang, William D Fiske
Endo Pharmaceuticals Inc, Chadds Ford, PA, USA
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 (AUC0–t), AUC from time 0 to infinity (AUC0–inf), and maximum plasma concentration (Cmax) 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 AUC0–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 Cmax (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 AUC0–t, AUC0–inf, and Cmax 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
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]