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      Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

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          Abstract

          Background

          XARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed.

          Methods

          This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP.

          Results

          Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food.

          Conclusion

          The findings from this study suggest that ER OC/APAP can be administered with or without food.

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          Most cited references 36

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          Pharmacology of oral combination analgesics: rational therapy for pain.

          No single analgesic agent is perfect and no single analgesic can treat all types of pain. Yet each agent has distinct advantages and disadvantages compared to the others. Hence, clinical outcomes might be improved under certain conditions with the use of a combination of analgesics, rather than reliance on a single agent. A combination is most effective when the individual agents act through different analgesic mechanisms and act synergistically. By activating multiple pain-inhibitory pathways, combination analgesics can provide more effective pain relief for a broader spectrum of pain, and might also reduce adverse drug reactions. This overview highlights the therapeutic potential of combining analgesic medications with different mechanisms of action, particularly a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen with an opioid or tramadol.
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            Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults.

            Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review that concluded, based on limited data, that all doses of oxycodone exceeding 5 mg, with or without paracetamol, provided analgesia in postoperative pain, but with increased incidence of adverse events compared with placebo. Additional new studies provide more reliable estimates of efficacy and harm.
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              • Article: not found

              Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial.

              To compare the efficacy and safety of controlled release oxycodone given every 12 h around the clock with immediate release oxycodone-acetaminophen (APAP) given 4 times daily for osteoarthritis (OA) pain. Adults (n=167) with moderate to severe OA pain despite regular use of nonsteroidal antiinflammatory drugs (NSAID) entered open label titration for 30 days with immediate release oxycodone qid; 107 qualified for randomization to double blind, parallel group treatment for 30 days with placebo, controlled release oxycodone, or immediate release oxycodone-APAP. Following titration with immediate release oxycodone, mean (SE) pain intensity (0, none to 3, severe) decreased from 2.44 (0.04) to 1.38 (0.05) (p=0.0001), and quality of sleep (1, very poor; 5, excellent) improved from 2.58 (0.08) to 3.57 (0.07) (p=0.0001). Mean dose was about 40 mg/day. Pain intensity and quality of sleep were significantly improved in both active groups compared with the placebo group (p< or =0.05) during the double blind trial. Pain intensity and sleep scores were comparable in both active groups during double blind treatment. Nausea (p=0.03) and dry mouth (p=0.09) were less common with controlled release oxycodone than immediate release oxycodone-APAP. Controlled release oxycodone q12h and immediate release oxycodone-APAP qid, added to NSAID, were superior to placebo for reducing OA pain and improving quality of sleep. The active treatments provided comparable pain control and sleep quality. Controlled release oxycodone was associated with a lower incidence of some side effects.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                19 August 2014
                : 8
                : 1125-1134
                Affiliations
                [1 ]Clinical Pharmacology and Pharmacokinetics, Hazelwood, MO, USA
                [2 ]Clinical Operations, Hazelwood, MO, USA
                [3 ]Research and Development, Hazelwood, MO, USA
                [4 ]Clinical Affairs, Mallinckrodt Inc., Hazelwood, MO, USA
                Author notes
                Correspondence: Krishna Devarakonda, Department of Clinical Pharmacology and Pharmacokinetics, Mallinckrodt Inc., 675 James McDonnell Blvd 302-3-W, Hazelwood, MO 63042, USA, Tel +1 314 654 3364, Fax +1 314 654 9364, Email krishna.devarakonda@ 123456mallinckrodt.com
                Article
                dddt-8-1125
                10.2147/DDDT.S64261
                4145823
                25170252
                © 2014 Devarakonda et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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