Abstract
Background: ALO-02, an opioid formulation intended to deter abuse, comprising capsules filled with pellets of extended-release oxycodone hydrochloride, an opioid, surrounding sequestered naltrexone hydrochloride, an opioid antagonist. This study compared oxycodone pharmacokinetics following ALO-02 (oxycodone/naltrexone 40 mg/4.8 mg) versus immediate-release oxycodone (IRO) tablets (20 mg). Methods: This was an institutional review board–approved, open-label, single-dose, randomized, two-way crossover study in 14 healthy fasted adults (aged 18 to 55 years). Plasma concentrations of oxycodone, naltrexone, and 6-β-naltrexol were determined. Maximum plasma concentration (Cmax), area under the plasma concentrationtime profile from time 0 to infinity (AUCinf) and to the last quantifiable concentration (AUClast), time to Cmax (Tmax), and terminal half-life (t1/2) were determined. Adverse events (AEs) were recorded throughout the study. Results: Median oxycodone Tmax was prolonged (12 versus 1 hours) and mean t1/2 was longer (7.2 versus 4.6 hours) for ALO-02 versus IRO. ALO-02/IRO ratio (90% confidence interval [CI]) of adjusted geometric means for dose-normalized AUCinf was 107.2% (96.7%, 118.8%), with CI contained within equivalence limits of 80%–125%. Dose-normalized ALO-02/IRO Cmax ratio (90% CI) was 33.0% (28.8%, 37.9%). Following ALO-02 administration, plasma naltrexone concentrations were below the limit of quantification (BLQ; 4.00 pg/mL), and 6-β-naltrexol concentrations were BLQ (4.00 pg/mL) in >50% of participants or generally low (<50.0 pg/mL). Most AEs were mild, with nausea and dizziness being most frequent. Conclusion: Pharmacokinetic comparisons indicate equivalent oxycodone bioavailability under fasted conditions. The lower Cmax and longer Tmax and t1/2 observed for ALO-02 versus IRO are consistent with the extended-release profile of ALO-02 formulation. Low naltrexone and 6-β-naltrexol concentrations indicated successful sequestration of naltrexone in ALO-02.
Highlights
Opioid analgesics are effective medications available to treat acute pain, most notably of surgical origin, and to alleviate chronic pain associated with terminal or non-terminal conditions in carefully selected and monitored patients [1,2]
At approximately 2 hours after receiving immediate-release oxycodone (IRO) 20 mg, this participant experienced an Adverse Event (AE) of gastroenteritis, which was mild and deemed not related to study drug, as well as dizziness and headache, which were both mild in severity
Another participant treated with IRO 20 mg was deemed an influential statistical outlier, with studentized residual < -3 for Cmax as well as AUCinf; PK results following IRO treatment for this outlier subject were excluded from the summary statistics and analyses
Summary
Opioid analgesics are effective medications available to treat acute pain, most notably of surgical origin, and to alleviate chronic pain associated with terminal or non-terminal conditions in carefully selected and monitored patients [1,2]. ER opioid formulations are taken only once daily or twice daily, compared with every 4- to 6-hour dosing with conventional immediate-release (IR) formulations. Along with the increased popularity and availability of ER opioid formulations, misuse, abuse, and diversion of these medications has become a significant public health issue in the United States (US) [4,5,6]. Strategies are needed to address the medical need for pain relief while offering approaches to minimize prescription opioid abuse. One strategy is the development of new drug formulations intended to reduce the attractiveness to abusers and drug-liking qualities of conventional opioid formulations while still providing pain. ALO-02, an opioid formulation intended to deter abuse, comprising capsules filled with pellets of extended-release oxycodone hydrochloride, an opioid, surrounding sequestered naltrexone hydrochloride, an opioid antagonist. This study compared oxycodone pharmacokinetics following ALO-02 (oxycodone/naltrexone 40 mg/4.8 mg) versus immediate-release oxycodone (IRO) tablets (20 mg)
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