Relative Oral Bioavailability of Morphine and Naltrexone Derived From Crushed Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules Versus Intact

© 2010 Excerpta Medica Inc. All rights reserved. ABSTRACT Background: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extendedrelease morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphineinduced subjective effects, rendering the product less attractive for tampering. Objectives: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-β-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. Methods: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for ≥2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-β-naltrexol were measured 0 to 168 hours after administration. Morphine pharmacokinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [ln]transformed Cmax and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Results: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0– 102.5 kg). Plasma Cmax and AUC0–t of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h ⋅ pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h ⋅ pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory Relative Oral Bioavailability of Morphine and Naltrexone Derived From Crushed Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules Versus Intact Product and Versus Naltrexone Solution: A Single-Dose, Randomized-Sequence, Open-Label, Three-Way Crossover Trial in Healthy Volunteers