Food effects on the pharmacokinetics of morphine sulfate and naltrexone hydrochloride extended release capsules

Abstract

Morphine sulfate and naltrexone hydrochloride extended release capsules, indicated for chronic moderate-to-severe pain, contain extended-release morphine pellets with a sequestered naltrexone core. If pellets are tampered by crushing, naltrexone is released to reduce morphine-induced effects that appeal to opioid abusers. The primary objective of this study was to assess single-dose relative bioavailability of morphine when morphine sulfate and naltrexone hydrochloride extended release capsules were taken under fed and fasting conditions and when pellets were sprinkled on apple sauce. This was a single-center, randomized, open-label study in 36 healthy adult volunteers. Subjects took a 100-mg morphine sulfate and naltrexone hydrochloride extended release capsule intact with 240 mL water, under fed and fasted conditions, and when the capsule was opened and pellets were sprinkled over apple sauce and consumed without chewing; each treatment was separated by a 14-day washout. Plasma samples were collected just before dosing through 72 hours postdose for pharmacokinetic analyses of morphine, and through 168 hours postdose for naltrexone and its major metabolite 6-β-naltrexol. Morphine bioavailability was similar for all treatments. There was a lack of sprinkle effect (sprinkle vs. whole, fasted); 90% confidence intervals (CIs) of ratios of log-transformed least squares means for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) fell within 80%-125% boundaries. For the food effect, 90% CIs were within the boundaries for AUC, but C(max) was reduced and time to C(max) was delayed by 2.5 hours under fed conditions. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. Results indicated that morphine sulfate and naltrexone hydrochloride extended release capsules can be administered without regard to meals, and contents can be sprinkled over apple sauce and consumed without chewing by patients with difficulty swallowing.