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.
Author(s): Johnson FK, Stark JG, Bieberdorf FA, Stauffer J.
Affiliation(s): Alpharma Pharmaceuticals LLC, a wholly owned subsidiary of King Pharmaceuticals,
Inc., Bridgewater, New Jersey, USA. franklinkjohnson@yahoo.com
Publication date & source: 2010, Clin Ther. , 32(6):1149-64
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.
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