The Relative Unavailability of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules (EMBEDA~R) and an Extended Release Morphine Sulfate Capsule Formulation (KADIAN~R) in Healthy Adults Under Fasting Conditions

摘要

Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA~R, King Pharmaceuticals~R, Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a |x-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN~R, treatment B). Morphine pharmaco-kinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of In-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC_(0-t)) and AUC from time 0 to infinity (AUC_(omf)) and maximum serum concentration (C_(max)) for treatments A versus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC_(0-t) (102.2%; 98.6-105.9%), AUC_(inf) (97.4%; 91.2-104.1%), and C_(max) (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC_(0-t) and AUC_(inf) fell within the 80%-125% range, but the lower limit for C_(max) was 76.9%.