Abstract
MNK-795, a combination oxycodone (OC) and acetaminophen (APAP) analgesic (OC/APAP ER), is a bilayer product with immediate-release (IR) and extended-release (ER) properties. Two single-center, open-label, randomized, phase 1, crossover studies were conducted in healthy participants (N=48 for each trial) to characterize the pharmacokinetics (PK) and bioavailability of OC/APAP ER. Study 1 compared the single-dose PK and bioavailability following administration of 1 or 2 tablets of OC/APAP ER with an IR OC/APAP formulation. Study 2 assessed the single-dose PK and bioavailability of 2 tablets of OC/APAP ER compared with those of marketed forms of IR oxycodone, IR tramadol/APAP, and IR OC/APAP. Safety and tolerability were monitored. In both studies, OC/ APAP ER demonstrated a bimodal OC release pattern, with a rapid rise and no lag in plasma concentrations after dosing, followed by an ER period with concentrations peaking 3 to 4 hours postdose and extending over 12 hours. Acetaminophen concentrations also demonstrated an initial rapid rise but tapered off at 7 to 12 hours postdose. Bioavailability and overall exposure of oxycodone and acetaminophen were comparable between single doses of OC/APAP ER and IR comparators (2 doses, 6 hours apart). Adverse events were consistent with those seen with opioids.
Highlights
Opioid/acetaminophen (APAP) combination analgesics offer an established approach to multimodal pain management [1,2,3]
Both studies demonstrated that the overall exposure (AUC0-t; AUC0-inf) to both oxycodone and acetaminophen were comparable for OC/APAP ER administered once and IR formulations (IR oxycodone; IR tramadol/APAP; and IR OC/APAP) administered twice; 6 hours apart
The Tmax for IR oxycodone has been previously reported to be approximately 1.4 to 2.6 hours with 15 and 30 mg dosing [23,24]; which is consistent with a Tmax of 1.5 to 2 hours seen after the second dose in the current studies. In these single-dose PK studies; the bioavailability of oxycodone and APAP were generally comparable between OC/APAP ER (1 or 2 tablets once) and IR OC/APAP (1 tablet twice) administered under fasted conditions
Summary
Opioid/acetaminophen (APAP) combination analgesics offer an established approach to multimodal pain management [1,2,3]. By utilizing agents with complimentary mechanisms of action; these combination formulations are intended to be additive; which may allow for the management of pain at a lower dose of each component; potentially reducing the risk of concentration-dependent adverse events [1,4,5,6,7]. Oxycodone is a semisynthetic opioid analgesic with high bioavailability with 60% to 87% of oral dose from IR formulation reaching systemic circulation [21,22]. Extendedrelease (ER) oxycodone formulations are designed to maintain plasma concentrations of oxycodone for longer periods; thereby permitting less frequent dosing [22,25,26]. Fewer daily doses has been shown to provide some benefit over more frequently dosed agents by reducing the pill burden and improving treatment adherence [25,27,28,29,30]
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