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*

摘要: 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 morphine pellets with a sequestered core of opioid antagonist naltrexone. MS-sNT was designed so that if product is tampered crushing, becomes bioavailable mitigate morphine-induced subjective effects, rendering less attractive tampering. Objectives: The primary aim this study compare oral bioavailability its metabolite 6-β-naltrexol, derived from crushed solution. This also assessed relative capsules whole, intact product. Methods: single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial conducted healthy volunteers. Adults admitted center underwent 10-hour overnight fast before drug administration. Each subject received all 3 following treatments, 1 per session, separated 14-day washout: (crushed ≥2 minutes mortar pestle) 60-mg capsule (60 mg morphine/2.4 naltrexone); capsule; HCl (2.4 mg) Plasma concentrations 6-β-naltrexol were measured 0 168 hours after pharmaco-kinetics whole determined 72 analysis based on conventional FDA criteria assuming bioequivalence; is, 90% CIs ratios geometric means (natural logarithm [In]-transformed C max AUC) fell within range 80% 125%. Subjects physical examinations, clinical laboratory tests, ECG at screening discharge monitored adverse events (AEs) throughout study. Results: Of 24 subjects enrolled study, 23 completed it. Most white (79%) male (63%); mean (SD) age 39.3 (11.2) years weight 77.6 (13.5) kg (range, 55.0102.5 kg). AUC 0-t administration (579 pg/mL 1811 h · pg/mL, respectively) solution (584 1954 pg/mL) not significantly different; 83.8% 116% 83.3% 102%, meeting regulatory requirements bioequivalence population. concentration below lower limit quantitation (4.0 (96%) different whether (163 ng/mL) or administered (174 ng/mL), but numerically higher (24.5 vs 7.7 T shorter (2.00 7.03 hours) versus whole. most commonly reported AEs nausea (8/23 [35%], 10/24 [42%], 3/23 [13%] crushed, groups, emesis (6 [26%], 7 [29%], 2 [9%]). Conclusions: In single-dose when appeared be completely released available effects. When an fashion while remained sequestered.