PMID- 20637968 OWN - NLM STAT- MEDLINE DCOM- 20101116 LR - 20131121 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 32 IP - 6 DP - 2010 Jun TI - 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. PG - 1149-64 LID - 10.1016/j.clinthera.2010.05.011 [doi] AB - 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 extended-release 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 morphine-induced 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-beta-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 >or=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-beta-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics 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 [In]-transformed C(max) 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, 55.0102.5 kg). Plasma C(max) and AUC(0-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 requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC(0-t) was not significantly different whether MS-sNT was crushed (163 h . ng/mL) or administered whole (174 h . ng/mL), but C(max) was numerically higher (24.5 vs 7.7 ng/mL) and T(max) was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). CONCLUSIONS: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered. FAU - Johnson, Franklin K AU - Johnson FK AD - Alpharma Pharmaceuticals LLC, a wholly owned subsidiary of King Pharmaceuticals, Inc., Bridgewater, New Jersey, USA. franklinkjohnson@yahoo.com FAU - Stark, Jeffrey G AU - Stark JG FAU - Bieberdorf, Frederick A AU - Bieberdorf FA FAU - Stauffer, Joe AU - Stauffer J LA - eng PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Delayed-Action Preparations) RN - 0 (Drug Combinations) RN - 0 (Narcotic Antagonists) RN - 0 (Narcotics) RN - 49625-89-0 (6 beta-hydroxynaltrexone) RN - 5S6W795CQM (Naltrexone) RN - 76I7G6D29C (Morphine) SB - IM MH - Administration, Oral MH - Adult MH - Area Under Curve MH - Biological Availability MH - Cross-Over Studies MH - Delayed-Action Preparations MH - Drug Combinations MH - Female MH - Humans MH - Male MH - Middle Aged MH - Morphine/adverse effects/blood/*pharmacokinetics MH - Naltrexone/adverse effects/analogs & derivatives/blood/*pharmacokinetics MH - Narcotic Antagonists/adverse effects/blood/*pharmacokinetics MH - Narcotics/adverse effects/blood/*pharmacokinetics EDAT- 2010/07/20 06:00 MHDA- 2010/11/17 06:00 CRDT- 2010/07/20 06:00 PHST- 2010/03/12 00:00 [accepted] PHST- 2010/07/20 06:00 [entrez] PHST- 2010/07/20 06:00 [pubmed] PHST- 2010/11/17 06:00 [medline] AID - S0149-2918(10)00174-8 [pii] AID - 10.1016/j.clinthera.2010.05.011 [doi] PST - ppublish SO - Clin Ther. 2010 Jun;32(6):1149-64. doi: 10.1016/j.clinthera.2010.05.011.